RO119830B1 - Cephalosporine antibiotics - Google Patents

Abstract

The present invention relates to cephalosporine antibiotics, to pharmaceutical compositions comprising these antibiotics, as well as to their use. These compounds have antibiotic activity against a wide range of organisms, including the organisms resistant to conventional beta-lactamic antibiotics.

Description

The present invention relates to cephalosporin antibiotics, to antibacterial compositions containing these compounds, and to their use in the manufacture of a medicament for the treatment of bacterial infections.

Over the past three decades, a variety of antibiotics have become available for clinical use. One class of antibiotics that has seen a remarkable increase are the cephalosporins, over 70 of them being entered in clinical use, for the treatment of bacterial infections in mammals, since 1965. Cephalosporins show their antibacterial activity, by inhibiting the bacterial peptidoglycan and have been extremely effective in treating a wide range of bacterial infections.

Cephalosporins that are considered to have antibacterial activity are described in US 3992377 and US 4256739.

The widespread spread and non-discriminatory use of these antibiotics has led to a rapid increase in the number of bacterial strains that are resistant to these compounds. Most importantly, this resistance has emerged among clinically important microorganisms, which threaten to limit the use of currently available cephalosporin antibiotics. In particular, species resistant to Salmonella S., Enterobacteriaceae and Pseudomonas have emerged, which threatens to cancel many of the steps taken to reduce mortality and morbidity due to bacterial infections.

Bacterial resistance to cephalosporins follows three important pathways:

a) the evolution of t-efa-lactamases capable of inactivating the beta-lactam ring of cephalosporins;

b) decreased penetration of cephalosporins into bacteria, due to changes in bacterial cell wall composition and weak binding to penicillin-related proteins (PBPs).

The latter pathway is especially important, as the binding of beta-lactamases to penicillin-related proteins is essential for inhibiting bacterial cell wall biosynthesis. Certain gram-positive bacteria, namely methicillin-resistant Staphylococcus aureus (MRSA - Methiclilin - Staphylococccus Aureus resistant) and enterococci are very resistant to befa-lactam antibiotics. The resistance to MRSA is due to the presence of elevated levels of unusual PBP, PRP 2a, which are insensitive or weakly bound to betalactam antibiotics. The activity of beta-lactam antibiotics against organisms containing PBP 2a has been shown to correlate well with the binding affinity of the antibiotic to PBP 2a. Currently, the glycopeptides vancomycin and teicoplanin are primarily used for methicillin-resistant Staphylococccus aureus bacteria. Chinolinic and some carbapenem-based antibodies, such as imipenem, have been reported to be active against methicillin-resistant Staphylococccus aureus species, but their use is restricted due to the emergence of methicillin-resistant Staphylococccus aureus species.

A number of experimental compounds, which may be used as antibacterials against methicillin-resistant Staphylococccus aureus, or as anti-heterozygous bactericides, including glycylcyclines in J. Med., Have been described. Chem., 37, 1994, P.E. Sum et al., FK-037 in J. Antibiotics, 46, 359-361, 1993, H. Ohki et al, RP-59500 in Antimicro. Agents Chemother., 36, 856-9, 1992, S.K. Spangler et al., The everninomycin complex in Antimicro. Agents Chemother., 6,232-8,1974, W.E. Sanders et al., 2- (diaryl) -carbapenem, in US 5025006.3 (benzothiazolliltio) -cefem in EP-A-527686.3- (thiazolylthio) -carbacefem in J. Med. Chem., 36, 1971, 1993, R.J. Ternansky and US 5077287 and arbecacin in J. Antibiotics, 46, 531,1993, S. Kondo.

In the international publication WO 96/26966, recent developments are described in terms of the compounds, compositions and methods of treatment of infections in mammals, which come from bacteria resistant to beta-lactam antibiotics.

EN 119830 Β1 in EP 0002765, cephalosporin derivatives, the process for their preparation 1 and their use in combating bacterial infections are described.

EP 0055466 refers to novel cefem compounds, having high antimicrobial activity, 3 to a process for their preparation, as well as to a pharmaceutical composition containing these compounds. 5 in EP 0055465, describes 7-acylaminocephalosporanic acid derivatives and their pharmaceutically acceptable salts with high antimicrobial activity. 7

The technical problem, which the present invention solves, is to provide new cephalosporin antibiotics, for the treatment of bacterial infections and, in particular, infections from 9 bacteria that have acquired resistance to conventional beta-lactam antibiotics. The compounds should have a minimum inhibitory concentration (MIC - Minimum Inhibitory Concentration), which is below 50%, preferably below 10% and most preferably less than 1% of the minimum inhibitory concentration of cefotaxim, or imipenem for a resistant organism. in beta-lactam, preferably 13, a methicillin-resistant Staphylococccus aureus organism or an ampicillin-resistant Enterococci organism.

The present invention relates to a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from the group consisting of -NHC (O) ZR ³ , -NR ⁴ R ⁵ , and

Z is selected from the group consisting of -CH ₂ (X) _m -, -C (NOR ⁶ ) -, -CH (OR ⁷ ) -, -C (CHCO ₂ R ⁸ ) - and -CH (NR ⁹ R ¹⁰ ) -; 29

X is selected from the group consisting of oxygen and sulfur;

m is selected from the group consisting of 0 and 1; 31

R ³ is selected from the group consisting of cyan, Ο, -Οθ alkyl which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromine, fluorine, chlorine, iodine, mer-capto or thio, cyano, alkylthio Ο, -Οθ, heterocycle selected from the group comprising fur, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzofuranil and dibenzothienyl, aryl C ₆ -C ₁₄ , he-35 teraryl, carboxyl, alkoxycarbonyl C, -C ₆ , C, -C _6, C ₂ -C ₆ alkenyl, nitro, amino, C, -C _e, and amido; aryl C ₆ -C ₁₄ , which may be substituted with one or more substituents selected from group 37 consisting of hydroxyl, bromine, fluorine, chlorine, iodine, mercapto or thio, cyano, alkylthio Ο, -Οθ, heterocycle selected from the group comprising fur, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazoly, piperazine-39, nil, dibenzofuranil and dibenzothienyl, aryl C ₆ -C ₁₄ , heteroaryl, carboxyl, alkoxycarbonyl Ο, -Οθ, alkyl Ο, Οθ, alkenyl C ₂ -C ₆ , nitro, amino, alkoxyl C, -C ₆ and amido; aryl C ₆ -C, ₄ , which may be substituted by one 41 or more substituents selected from the group consisting of hydroxyl, bromine, fluorine, chlorine, iodine, mercapto or thio, cyano, cyanamido, C 1 -C ₆ alkylthio, heterocycle selected from the group comprising furyl, 43 thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzofuranil and dibenzothienyl, aryl C ₆ -C, ₄ , heteroaryl, carboxyl, alkoxycarbonyl C, -C ₆ , alkyl C, -C ₆ , C ₂ -C ₆ alkenyl, nitro, amino, 45 C, C ₆ -alkoxyl and amido; a heterocycle selected from the group comprising fur, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzoluranyl and dibenzothienyl, which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromine, fluorine, fluorine, iodine, mercapto or thio, cyan, cyanamide, C 1 -C ₆ alkylthio, heterocycle, C ₆ -C ₁₄ aryl, heteroaryl, carboxyl, oxo, 49

RO 119830 Β1 alkoxycarbonyl Ο, -Cg, alkyl Ο, -Οθ, C ₂ -C ₆ alkenyl, nitro, amino, alkoxyl Ο, -Ο ₆ and amido; or a heteroalkyl group (RHetAr), wherein R is C 1 -C 6 alkyl; HetAr is an aromatic heterocycle defined as above), and (CH ₂ ) _n T, where n is 1 to 6,

T is selected from the group consisting of amino NRR ', wherein R and R' may be alkyl Ο, -Οθ, aryl C ₆ -C ₁₄ , or acyl C (O) R, wherein R is alkyl C, -C _G , amidino (C- or N- bonded), guanidino, and isothioureido, which may be substituted with C, -C ₆ alkyl, C ₆ -C ₁₄ aryl, hydroxyl, or amino, as defined above;

R ^{4 7} are independently selected from the group consisting of hydrogen, Ο, -Cg alkyl, C ₆ -C ₁₄ aryl and acyl, as defined above; wherein R ⁶ may also be a group forming a hydroxy group protected with the adjacent oxygen atom;

R ⁸ is selected from the hydrogen group, Ο, -Cg alkyl, C ₆ -C ₁₄ aryl;

R ⁹ and R ¹⁰ are independently selected from the group consisting of hydrogen, Ο, -Cg alkyl, acyl, as defined above, and heterocyclylcarbonyl (C (O) Het, wherein Het is a heterocycle as defined above. )

R ^z is selected from the group consisting of hydrogen, C 1 -C 6 alkyl which can be substituted as defined above, C 2 -C 6 alkenyl, which can be substituted with one or more functional groups selected from the group consisting of hydroxyl, bromine. , fluorine, chlorine, iodine, mercapto or thio, cyano, achylthio, -Cg, heterocycle, aryl C6-C14, heteroaryl, carboxyl, alkoxycarbonyl-C, -Cg, alkyl 0, -Cg, C2-C6 alkenyl, nitro, amino , alkoxyl Ο, -Ο6, and amido; aryl C6-C14 which may be substituted as defined above, a hetocycle which may be substituted as defined above, aralkyl (RAr wherein R is alkyl Ο, -Cg, which may be substituted as further defined above and Ar is C6-C14 aryl, which can be substituted as defined above), heteroaralkyl, and trialkylsilyl (R'RSi, wherein R, R 'and R are alkyl groups Ο, -Cg); or R ² is not present and the CO2 group to which they could be attached covers a negative charge;

ring G, H, J, L and M is a carbon, nitrogen or NR ¹¹ (quaternary ammonium heterocycle) containing a heterocycle selected from the group consisting of pyridinyl, piperazinyl, pyrimidinyl and pyrazinyl;

R ¹¹ is selected from the group consisting of H, halogen, C 1-6 alkyl, C 1 -C ₆ alkoxy, hydroxyl, amino as defined above, cyano, hydroxyalkyl Ο, -Cg, carboxamidoalkyl Ο, -Cg, aminoalkyl Ο, -Cg or alkyl -Ο, -Cg-quaternary ammonium, and quaternary heteroarylalkyl;

alk ₄ and alk ₂ are Ο, -Cg alkyl groups which can be independently substituted with a substituent selected from the group consisting of C1-Cg alkyl, hydroxyl, amino, as defined above, xi, -Cg, hydroxyalkyl Ο, -Cg and carboxamide;

p is 0.1, or 2;

R ⁹⁹ is selected from the group consisting of sulfur, SO, SO ₂ , NH, N-C 1 -C 6 alkyl, oxygen, C = C (c / s or trans), and C = C;

q is 1;

residues 0,1,2 or 3;

R ' ² is NR ¹³ R ¹⁴

RO 119830 Β1

R ¹³ -R ¹⁶ are independently selected from the group consisting of H, hydroxy, amino as defined above, amidino, C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, acyl, aminoacyl and phosphoryl and, taken together, can to form a 5 or 6 membered ring; and 3

R ' ⁷ is H, or alkyl Ο _Γ Οθ;

wherein alk ₂ and R ¹² , taken together, may form a non-aromatic 5 or 5 6 membered heterocycle, optionally substituted, which may be substituted, as defined above.

The invention also relates to a compound of formula II: 7

or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from the group consisting of -NHC (O) ZR ³ , -NR ⁴ R ⁵ , and 15

Z is selected from the group consisting of -CH ₂ (X) _m -, -C (NOR ⁶ ) -, -CH (OR ⁷ ) -, - (CHCO ₂ R ⁸ ) - 21 and -CH (NR ⁹ R ¹⁰ ) -;

X is selected from the group consisting of oxygen and sulfur; 23 m is selected from the group consisting of 0 and 1;

R ³ is selected from the group consisting of cyan, Ο, -Cg alkyl which may be substituted by one or more substituents selected from the group consisting of hydroxyl, bromine, fluorine, chlorine, iodine, mercapto or thio, cyano, alkylthio C, -C ₆ , heterocycle selected from the group comprising fur, thienyl, imide-27 zolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzofuranil and dibenzothienyl, aryl C ₆ -C ₁₄ , heteroaryl, carboxyl, alkoxycarbonyl Ο, -Οβ C 1 -C ₆ , C ₂ -C ₆ alkenyl, nitro, amino, C ₁ -C ₆ alkoxy and amido; aryl C ₆ -C ₁₄ which can be substituted with one or more substituents selected from the group consisting of hydroxyl, bromine, fluorine, chlorine, iodine, mercapto or thio, cyano, cyanamido, alkylthio 0, -Cg, 31 heterocycle selected from the group comprising fur, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzofuranyl and dibenzothienyl, aryl C ₆ -C ₁₄ , heteroaryl, carboxyl, alkoxycarbonyl 0, -33 C ₆ , alkyl Ο, -Οθ, alkenyl C ₂ - C ₆ , nitro, amino, alkoxyl Ο, -Οθ and amido; a heterocycle selected from the group comprising fur, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzofu-wound and dibenzothienyl, which may be substituted by one or more substituents selected from the group consisting of hydroxyl, chloro, iodo, mercapto or thio, cyano, cyanoamido, alkylthio 37 0, -C, heterocycle, C ₆ -C ₁₄ aryl, heteroaryl, carboxyl, alkoxycarbonyl C _r C ₆ alkyl, C, -C ₆ alkenyl, C ₂ C ₆ , nitro, amino, alkoxyl Ο, -Cg and amido; 39 a heterocycle selected from the group comprising fur, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzofuranil and dibenzothienyl, aryl C ₆ -C ₁₄ , heteroaryl, carboxyl, alkoxycarbonyl-41-bonyl Ο, -Cg, alkyl -C ₆ , alkenyl 0, -Cg, nitro, amino, alkoxyl Ο, -Οθ and amido; a heterocycle selected from the group comprising fur, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzofuranyl and dibenzothienyl, which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromine, fluorine, fluorine iodine, mercapto or thio, cyano, cyanamido, 45 Ο alkylthio, -Cg, heterocycle, C ₆ -C ₁₄ aryl, heteroaryl, carboxyl, oxo, C 1 -C ₆ alkoxycarbonyl, C 1 -C ₆ alkyl, C ₂ -C ₆ alkenyl , nitro, amino, alkoxyl Ο, -Ο ₆ and amido; or a heteroalkyl group (RHetAr), wherein R is 47 C, -C ₆ alkyl; HetAR is an aromatic heterocycle defined above), and (CH ₂ ) _n T, n is 1 to 6, 49

RO 119830 Β1

T is selected from the group consisting of amino NR'R, wherein R 'and R may be 0, -Cg alkyl, amidino (C-, or N- linked), guanidino, and isothioureido, which may be substituted with 0-alkyl. , -C aryl, C ₆ -C _u, hydroxyl, or amino as defined above;

R ⁴ ' ⁷ are independently selected from the group consisting of hydrogen, C 1 -C ₆ alkyl, C ₆ -C ₁₄ aryl and acyl, as defined above; wherein R ⁶ may also be a group which forms a hydroxy protecting group with adjacent oxygen;

R ⁸ is selected from the hydrogen group, alkyl Ο, -Ο ₆ , aryl C ₆ -C ₁₄ ;

R ⁹ and R ¹⁰ are independently selected from the group consisting of hydrogen, alkyl Ο, -ch, acyl, as defined above, and heterocyclylcarbonyl (C (O) Het, wherein Het is a heterocycle as defined above. )

R ² is selected from the group consisting of hydrogen, Ο, -Οθ alkyl which can be substituted as defined above, C 2 -C 6 alkenyl, which can be substituted with one or more functional groups selected from the group consisting of hydroxyl, bromine. , fluorine, chlorine, iodine, mercapto or thio, cyano, achylthio Ο, -Οθ, heterocycle, aryl C6-C14, heteroaryl, carboxyl, alkoxycarbonyl C, -C6, alkyl Ο, -Οθ, alkenyl C2-Cf, nitro, amino , alkoxyl Ο, -Cg, and starch; aryl C6-C14, which can be substituted as defined above, a heterocycle which can be substituted as defined above, aralkyl (Rar, wherein R is C, -C6 alkyl, which can be substituted as described defined above and Ar is C6-C14 aryl which can be substituted as defined above), heteroarylalkyl and trialkylsilyl (R'RSi, wherein R, R 'and R "are alkyl groups Ο, -Ο6); or R ² is not present and the CO2 group to which it could be linked carries a negative charge;

ring A, B, D, and E is a heterocycle containing a carbon, nitrogen, or sulfur atom selected from the group consisting of thienyl, imidazolyl, thiazolyl, thiadiazolyl, and pyrazolyl;

R ¹¹ is selected from the group consisting of H, halogen, Ο, -Cg alkyl, Ο, -Οθ, alkoxy, hydroxyl, amino, as defined above, cyano, hydroxyalkyl Ο, -Οθ, carboxamidoalkyl C, -C ₆ , amino acid Ο, -Οθ, or quaternary alkylammonium C, -C ₆ and heteroaryl-quaternary alkyl;

alk, and alk ₂ are Ο, -Cg alkyl groups, which can be independently substituted with a substituent selected from the group consisting of C, -C ₆ alkyl, hydroxyl, amino, as defined above, C 1 -C 6 alkoxy, hydroxyalkyl. Ο, -Cg and carboxamido;

over 0.1, or 2;

R ⁹⁹ is selected from the group consisting of sulfur, SO, SO ₂ , NH, N-C 1 -C 6 alkyl, oxygen, C = C (cis or trans), and C = C;

q is 1;

residues 0,1,2 or 3;

R ¹² is NR ¹³ R ¹⁴

R ¹³ -R ¹⁶ are independently selected from the group consisting of H, hydroxy, amino as defined above, amidino, C _r -C, cycloalkyl Ο, -Ο ₆ acyl, as defined above, aminoacyl, and phosphoryl and taken together can form a 5 or 6 membered ring; and

R ¹⁷ is H, or alkyl Ο, -Ο ₆ ;

RO 119830 Β1 in which white, and R ¹² taken together may form an optionally substituted 5 or 6 1 non-aromatic heterocycle.

The invention also relates to the use of the compounds according to the invention, to the manufacture of a medicament for the treatment of a mammal suffering from bacterial infection resistant to methicillin, or resistant to ampicillin. 5

Another object of the invention relates to an antibacterial composition for treating a bacterial infection resistant to methicillin, resistant to vancomycin or resistant to ampicillin. 7

The advantages of the present invention are that the cephalosporin antibiotics provided are effective for treating bacterial infections and, in particular, 9 infections from bacteria that have acquired resistance to conventional beta-lactam antibiotics, having a concentration minimum inhibitor (MIC- Minimum Inhibitory Concen- tration), below 50%, preferably below 10% and most preferably below 1% of the minimum inhibitory concentration of cefotaxim, or imipenem for a beta-lactam-resistant organism, preferably 13 a methicillin-resistant Staphylococccusaureus organism, or an ampicillin-resistant Enterococci organism.15

FIG. 1-5 presents the schematic diagrams of the compounds of the present invention.

FIG. 1 shows the preparation of cefem.17

FIG. 2 shows the preparation of C-substituent (7).

FIG. 3 shows the preparation of substituent-3.19

FIG. 4 presents the final assembly.

FIG. 5 shows deprotection and salt formation.21

Specific examples of heterocyclic groups known in the field of chemistry include:

In a preferred embodiment, compounds of formula I are preferred, wherein R 'is 41 -NHC (O) ZR ³ and / or R ³ is preferably C6-C14 aryl. or heterocycle, which can be substituted, and more preferably R ³ is selected from the group consisting of phenyl, thienyl, or furanyl, which can be substituted, as defined above, 2-aminothiazol-4-yl, 2 -amino-5-chlorothiazol-4-yl, and 2-aminothiadiazol-4-yl and / or Z is -C (NOR ⁶ ) -, and R ⁶ is selected from the group consisting of hydrogen and alkyl 0, - 45 C6, which can be substituted, as defined above, more preferably R ⁶ is selected from the group consisting of hydrogen, 2-fluoroethyl, cyclopropylmethyl, allyl, dichloroalyl, and-eethoperthyl, and R ³ is selected from the group consisting of phenyl. , 2-thienyl, 2-furyl, 2-aminothiazol-4-yl, 2-amino-5-chlorothiazol-4-yl, and 2-aminothiadiazol-4-yl. 49

RO 119830 Β1

An even more preferred embodiment of compounds of formula I includes those wherein R ⁶ is hydrogen or 2-fluoroethyl and R ³ is 2-aminothiazol-4-yl, or 2-amino-5-chlorothiazol-4-yl.

Preferred compounds of formula I are those in which

R ¹ is -NHC (O) ZR ³ ;

Z is -C (NOR ⁶ );

R ⁶ is hydrogen or fluoroethyl;

R ³ is a heterocycle, which can be substituted, as defined in claim 1;

R ² is hydrogen, or the CO ₂ group to which it may be attached is present, covers a negative charge;

G, H, L and M are carbon atoms;

J is nitrogen;

alk, is CH ₂ ;

p is 0 or 1;

R "is sulfur;

q is 1;

alk ₂ is CH ₂ ;

remains 2 or 3;

R ¹² is NH ₂ or NH ₃ +; and and are zero groups R ¹¹ and one group [(alkJ ^ R ^ talk ^ R ¹² ].

Examples of preferred compounds of formula I may be mentioned:

(7R) -7- [(Z-2- (2-amino-5-chloro-thiazol-4-yl) -2- (hydroxyamino) acetamido] -3- [3- (2-aminoetiltiometil) pyrid-4-ylthio] - 3-cefem-4-carboxylate, or a suitable salt, (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- [3- ( 2-aminoethylthiomethyl) pyrid-4-ylthio] -3-cefem-4-carboxylate, or a corresponding salt, (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- [3- (2-aminoethylthio) pyrid-4-ylthio] -3-cefem-4-carboxylate, or a corresponding salt, (7R) -7 - [(Z) - 2- (2-amino-5-chloro-thiazol-4-yl) -2- (hydroxyimino) acetamido] -3- [3- (2R-2-amino-2carboxamidoetiltiometil) pyrid-4-ylthio] -3-cephem-4 -carboxylate, or an appropriate salt, (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- [3- (2S -2-amino-2-carboxamidoethylthiomethyl) pyrid-4-ylthio] -3-cefem-4-carboxylate, or a corresponding salt, (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazole-4 -yl) -2- (hydroxyimino) acetamido] -3- [3- (2R-2-amino-3hydroxypropylthiomethyl) pyrid-4-ylthio] -3-cefem-4-carboxylate, or a suitable salt thereof re, (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- [3- (2S-2-amino-3-hydroxypropylthiomethyl) ) pyrid-4-ylthio] -3-cefem-4-carboxylate, or a corresponding salt, (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3- [3- (2-aminoethylthiomethyl) pyrid-4-ylthio] -3-cefem-4-carboxylate, or a corresponding salt, (7R) -7 - [(Z) -2 - (2-Aminothiazol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3- [3- (2-aminoethylthiomethyl) pyrid-4-ylthio] -3-cefem-4-carboxylate, or a corresponding salt thereof .

In another embodiment, a compound of the formula is preferred:

or a pharmaceutically acceptable salt thereof, wherein R ³⁴ is halogen or hydrogen;

RO 119830 Β1

R ⁵³ is selected from the group consisting of NH ₂ and protected amino; and 1

R ² , R ⁶ , G, J, L, M, R ¹¹ , alki, p, R ⁹⁹ , q, alk ₂ , r, and R ' ² are as defined above for compound of formula I. 3

Preferred compounds include compounds in which R ₂ is hydrogen, or is not present, and the CO ₂ group to which it may be attached covers a negative charge; 5

R ₃₄ is chlorine, or hydrogen;

R ⁶ is hydrogen, cyclopentyl, or fluoroethyl; 7

G, H, J, L, and M are selected to form 2-pyridyl, 3-pyridyl, 3-pyridyl, or 4-pyridyl;

R ¹¹ is hydrogen, halogen, or alkyl; 9 there is a single group [(alk ₁ ) _p (R ⁹⁹ ) q (alk ₂ ) r R ¹² )];

alki is CH ₂ ; 11 p is 0 or 1;

R is sulfur; 13 q is 1;

alk ₂ is CH ₂ , optionally substituted with hydroxy, hydroxyalkyl C, -C ₆ , or carboxamide; 15 remain 2; and

R ^{12 is} NH ₂ .17

Even more preferred compounds include compounds of the above formula, wherein R ³⁴ is chlorine, R ⁶ is hydrogen, and G, H, J, L, and M are selected to form 4-pyridyl. 19

Another embodiment relates to compounds of formula II, or a pharmaceutically acceptable salt thereof, wherein R ¹ is -NHC (O) ZR ³ and / or R ³ is aryl C ₆ - 21 C ₁₄ , or heterocycle, which may be substituted, as defined above for the compound of formula II. 2. 3

Preferred compounds of formula II include those wherein R ³ is selected from the group consisting of phenyl, thienyl, or furanil, which may be substituted, as defined above for compound 25 of formula II, 2-aminothiazol-4-yl , 2-amino-5-chlorothiazole-4yl, and 2-aminothiadiazole-4yl.

Preferred compounds of formula II also include those wherein Z is -C (NOR ⁶ ), and R ⁶ is selected from the group consisting of hydrogen, and alkyl Ο, -Cg, which can be substituted, as defined for the compound of formula II. 29

Also preferred are compounds of formula II wherein R ⁶ is selected from the group consisting of hydrogen, 2-fluoroethyl, cyclopropylmethyl, allyl, dichloroalyl, and cyclopentyl, and R ³ is selected from the 31-membered group consisting of phenyl, 2-thienyl. , 2-furyl, 2-aminothiazol-4-yl, 2-amino-5-chlorothiazol-4-yl, and 2-aminothiadiazol-4-yl. Still more preferred are compounds of formula II wherein R ⁶ is hydrogen, or 2-fluoroethyl and R ³ is 2-aminothiazol-4-yl, or 2-amino-5-chlorothiazol-4-yl. In another embodiment, a compound of the formula is preferred:

or a pharmaceutically acceptable salt thereof, wherein

R ³⁴ is halogen, or hydrogen; 45

R ⁵³ is selected from the group consisting of NH ₂ , NH ₃ + and also protected amino;

R ² , R ⁶ , A, B, D, E, R ¹¹ , alk7 p, R ⁹⁹ , q, alk2, r, and R ¹² are as defined above. 47

An even more preferred embodiment includes compounds of the above formula, wherein R ³⁴ is chlorine;

RO 119830 Β1

R ² is hydrogen, or it is not present and CO ₂ to which it could be linked carries a negative charge;

R ⁶ is hydrogen;

A, B, D, and E are selected to form thiazole and thiadiazole;

R ' ¹ is hydrogen, halogen or alkyl;

alk, is CH ₂ ;

p is 0 or 1;

R is sulfur;

alk ₂ is CH ₂ ;

remains 2 or 3; and

R ¹² is NH ₂ or NH ₃ +.

As used herein the term "alkyl" means branched or unbranched hydrocarbon chains, preferably containing from 1 to 6, more preferably from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, n-propyl, isopropyl. , n-butyl, sec-butyl, isobutyl, tertiary butyl and 2-methylpentyl. These groups may optionally be substituted with one or more functional groups which are routinely attached to such chains, such as, for example, hydroxyl, bromine, fluorine, chlorine, iodine, mercapto, or thio, cyano, alkylthio, heterocycle, aryl, heteroaryl, carboxyl, alkoxycarbonyl and optionally substituted isothioureido, amidino, guanidino and the like to form alkyl groups, such as estetrifluoromethyl, 3-hydroxyhexyl, 2-carboxypropyl, 2-guanidinoethyl, '-dimethylisothiouroniumpropyl and the like.

The term "alkenyl" means an alkyl group, as defined above, having at least one double bond, for example, allyl, 3-hydroxy-2-buten-1-yl, 1-methyl-2-propen-1-yl and the like.

The term aryl represents a chain of carbon atoms, which forms at least one aromatic ring, preferably having about 6 to 14 carbon atoms, such as, for example, phenyl, naphthyl, indenyl and the like. and which may be substituted with one or more functional groups which are conventionally attached to such chains, such as, for example, hydroxyl, bromine, fluorine, chlorine, iodine, mercapto, or thio, cyano, cyanoamido, achylthio, heterocycle, aryl, heteroaryl, carboxyl, alkoxycarbonyl, alkyl, alkenyl, nitro, amino, alkoxy, amido and the like to form aryl groups, such as diphenyl, iododiphenyl, methoxydiphenyl, antrinyl, bromophenyl, iodophenyl, chlorophenyl, hydrophenyl, hydrophenyl, hydroxyphenyl, chlorophenyl. methoxyphenyl, formylphenyl, acetylphenyl, trifluoromethylthiophenyl, trifluoromethoxyphenyl, alkylthiophenyl, trialkylammoniumphenyl, amidophenyl, thiazolylphenyl, oxazolylphenyl, imidazolylphenylphenyl, imidazolylmethylphenyl, imidazolylmethylphenyl, imidazolylmethylphenyl Nile, triazolylphenyl and the like.

The term "heterocycle" represents a chain of carbon atoms and at least one different carbon atom, which together form one or more aromatic or non-aromatic rings, preferably having between 6 and 14 atoms, such as for example, fur, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzofuranil, dibenzothienyl. These rings may optionally be substituted with one or more functional groups, which are conventionally attached to such rings, such as, for example, hydroxyl, bromine, fluorine, chlorine iodine, mercapto, or thio, cyano, cyanoamido, alkylthio, heterocycle, aryl, heteroaryl, carboxyl, oxo, alkoxycarbonyl, alkyl, alkenyl, nitro, amino, alkoxy, amido and the like, to form rings such as, for example, 2-aminothiazole-. 4-yl, 2-amino-5-chlorothiazol-4-yl, 2-amino-thiazol-4-yl, 2,3-dioxopiperazinyl, 4-alkylpiperazinyl, 2-iodo-3-dibenzofuranyl and 3-hydroxy-4- dibenzothienil and the like.

The term heteroaromatic or heteroaryl (HetAr) represents an aromatic heterocycle as defined above.

_____ The term heterotricycle represents an aromatic heterocyclic substituent, as defined above, comprising three aromatic rings.

RO 119830 Β1

The term heterocyclocarbonyl denotes the group -C (O) Het, where Het is a 1-ring hetero, as defined above.

The term alkoxyl represents an -OR group, wherein R is alkyl, as defined above 3, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, trifluoromethoxy, 3-hydroxyhexyloxy, 2-carboxypropyloxy, 2-fluoroethoxy, carboxymethoxy and cyano-5-butyloxy, and the like.

The term "alkylthio" represents a -SR group, wherein R is alkyl as defined above 7, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, isobutylthio, tert-butylthio, trif uoromethylthio, 3-Hydroxyhexy Itio, 2-carboxypropiitio, 2-fuoroethylthio, carboxymethylthio and cyano-9-butylthio and the like.

The term acyl represents -C (O) R groups, wherein R is alkyl as defined above, such as formyl, acetyl, propionyl or butyryl.

The term aryloxy represents -Or groups, in which Ar is an aryl group, as defined above.

The term aralkyl represents -Rar groups, in which R is alkyl and Ar is aryl, both 15 as defined above.

The term "heteroarylalkyl" 'represents -RhetAr groups, wherein R is alkyl and HetAr is 17 heteroaryl, as defined above.

The term "trialkylsilyl" represents an RR'RSi group, wherein R, R 'and R are alkyl, as defined above.

The term trialkylammonium represents a group [RR'R “N-] ₁ in which R, R 'and R are alkyl, 21 as defined above.

The term "amino represents an NRR 'group, wherein R and R' may independently be 23 alkyl, aryl, or acyl, as defined above.

The term carboxamido represents a -C (O) NRR 'group, wherein R and R' may independently be alkyl, aryl, or acyl, as defined above, or hydrogen.

The term "cyanamido" refers to -NH-C = N groups. 27

The term "beta-lactam resistant bacteria" refers to bacteria against which the beta-lactam antibiotic has a minimum inhibitory concentration (MIC) greater than 32 mg / ml. The term methicillin-resistant bacteria refers to bacteria that are methicillin-resistant. Examples of such bacteria are given in Table 1 and Meth ^R is identified. 31 The term "methicillin-sensitive bacteria" refers to bacteria that are methicillin-sensitive. Examples of such bacteria are given in Table 1 and Meth ^s is identified. The term prodrug refers to an agent that is converted to a source drug in vivo. Under certain conditions such agents may be easier to administer than the source drug (mother). For example, the prodrug may be bioavailable by oral administration, while the parent drug is not, or the prodrug may improve solubility to allow intravenous administration.

Synthesis of compounds of formula II 39

The compounds of the present invention can be readily prepared according to the following schemes. However, it must be admitted that other synthetic pathways are available for obtaining the compounds of the present invention and that the following synthetic pathways are merely examples and do not constitute a limitation. It must be admitted further that different strategies of protection and deprotection can be used which represent standard methods in current practice (see, for example, Green and Wuts). Those skilled in the art know that choosing a certain protecting group (eg, a carboxy protecting group) depends on the stability of the protected core in relation to the following reaction conditions. 47 In general, the synthesis of cephalosporins in the present patent application can be accomplished, using well-known methods and easy-to-obtain materials (see, for example, March; Larock, 49

RO 119830 Β1

Comprehensive Organic transformations (VCH Publishers, 1989) and G. I. Georg, The Organic Chemistry of beta-lactams, (VCH 1992), each of which is incorporated herein by reference). As shown below, in Scheme 1, treating cefem triflate 1 with the desired nucleophilic 2-thiolate, optionally protected, using standard methods, such as those described by Farina et al. in J. Med. Chem., 54, 4962, 1989 and in US Pat. No. 4870168 (both incorporated herein by reference), provide 3-thio derivative 3. Subsequent deprotection, using methods known to those skilled in the art, results in 4-carboxyphem 4, which is biologically active. .

The R ¹ substituent may be any of the groups described above and are either commercially available and obtainable (for example, from Aldrich, Milwaukee, WI), or may be prepared using known techniques (see, for example, March; Larock). These groups can be substituted for those present on the starting materials by a variety of well-known techniques (see, for example, Barett, JCS, Perkin I, 1969, (1979), or Chauvette, J. Org. Chem., 36, 1259, (1971) (both incorporated herein by reference), such as transaminating an existing substituent with a desired substituent, or hydrolytic removal of an existing substituent followed by reaction with a suitable reactive form of the desired substituent, such as a and in this case the reagents and techniques used are obvious to the artisanalists in the field.

The carboxyl group R ² may be that of the protective groups responsible for the reductive cleavage, such as benzyl, p-, or o-nitrobenzyl, 2,2,2-trichloroethyl, allyl, cinnamyl, benzhydryl, 2-chloroalkyl and the like. Alternatively, R ² may be a protective group responsible for acid cleavage, such as tertiary butyl, tertiary amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, trimethylsilyl, tertiary butyldimethylsilyl, phenacyl, 3- (trimethylsilyl) ethyl, benzyl, 4- (or 2-) -methoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, methoxymethyl, benzhydryl, or 3,3-dimethylalyl. Preferred protecting groups are p-methoxybenzyl, p-nitrobenzyl, allyl and benzhydryl. These groups may be attached to an unprotected carboxyl group of the starting material for obtaining cephalosporin using known reagents and techniques, such as those described by Green and Wuts.

Synthesis of compounds of formula I ____

Compounds of general formula I are prepared in a similar manner to those of general formula II.

In most cases, a key phase is coupling a heteroarylthiolate substituted with

RO 119830 Β1 triflate cefem 1, or functionally equivalent cefem having an alternative group 1 which leaves the molecule at C3. Compounds of formula I, wherein the ring containing G, H, J, L and M is 4-pyridyl, may also be prepared, as exemplified in FIG. 4. 3

Pharmaceutical applications and preparations

According to this invention, a therapeutically or pharmaceutically effective amount of a cephalosporin and especially of a compound of general formula I or II is administered to a mammal suffering from resistant bacterial infection. methicillin 7 (or other 3-lactam-resistant bacterial infections, such as vancomycin-resistant, or ampicillin-resistant infections), generally Staphylococcus aureus, in an effective amount 9 to remove, at least partially, the infection. In particular, infections resulting from species (strains) having activity similar to species, such as Staphylococcus aureus 11 Col (Meth ^R ) (lac-), Staphylococcus aureus 76 (Meth ^R ) (lac +), E. faecium ATCC, are important. 35667, or E. faecalis ATCC 29212. As shown, these compounds are also effective against bacteria sensitive to methicillin, vancomycin and / or ampicillin and are therefore used in such compositions and treatment methods. . 15

The compositions containing the compound (respectively compounds) of the present invention may be administered for prophylactic and / or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from an infection, as described above, in an amount sufficient to cure, or at least partially stop the symptoms of the infection. The appropriate amount to perform this is defined as quantity, or therapeutically effective dose. ” The effective amounts for such use depend on the severity and course of the infection, previous therapy, the patient's health and response to the medication, as well as the prescriptions of the treating physician. 23 In prophylactic applications, the compositions containing the compounds of the present invention are administered to the patient susceptible to the risk of a certain infection. Such an amount is defined as a quantity, or a prophylactically effective dose. For such use, the precise quantities are also depending on the health of the patient, 27 body weight and others. With the improvement of the patient's condition, a maintenance dose is administered if necessary. Thereafter, the dose or frequency of administration, 29 or both, may be reduced, depending on the symptoms, to a level at which the improved condition is maintained. When the symptoms have been alleviated to the desired level, treatment may be discontinued. Patients may, however, require intermittent treatment on a long-term basis after recurrence of the symptoms of the disease. Generally, a suitable effective dose of a compound of the present invention is in the range of 0.1 to 1000 mg per container per day, preferably in the range of 35 to 1 to 100 mg per day. The desired dose is preferably presented in one, two, three, four, or more sub-doses administered at appropriate intervals during a day. These sub-doses may be administered as unit dosage forms, for example, containing 5 to 1000 mg of active ingredient per unit dose form. The compounds of the present invention can be administered in amounts ranging from 39 to about 2.0 mg / kg to about 250 mg / kg patient body weight and this once up to four times daily. 41

Although it is possible to administer the active ingredient of the present invention alone, it is still preferred that it be presented as part of a pharmaceutical formulation. The formulations of the present invention comprise at least one compound, or inhibitor of the present invention in a therapeutically or pharmaceutically effective dose together with one or more pharmaceutically acceptable or therapeutically acceptable carrier agents. Solid carriers include, for example, starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin and optionally other therapeutic ingredients as well. Liquid carrier agents include, for example, sterilized water, polyethylene glycols, nonionic surfactants and comestible oils 49

EN 119830 Β1 balls, such as corn oil, peanut oil and sesame oil. In addition, various adjuvants such as those conventionally used in formulations may also be included. For example, flavorings, dyes, preservatives and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA. Other aspects are described, for example, by Gilman et al. (Ed. 1990), Goodman and Gilman, in The Pharmaceutical Basis of Therapeutics, 8th ed., Pergamon Press; and Remington '. This describes the methods of administration, for example, oral, intravenous, intraperitoneal, or intramuscular administration and the like. The pharmaceutically acceptable carrier agents include water, saline, buffers and other compounds described, for example, in the Merck Index, Merck & Co., Rahway, NJ. In general, preferred routes of administration are intravenous and intraperitoneal.

These pharmacological agents can be in a variety of forms. These include, for example, solid, semi-solid and liquid dosage forms, such as tablets, pills, powders, liquid solutions and suspensions, liposomes, injectable and infusion solutions. Preferred forms depend on the mode of administration desired and the therapeutic application. In general, a pharmaceutically acceptable salt of the compound is used to simplify the preparation of the composition. Preferred salts include sodium, potassium, arginine, glycine, alanine, threonine. They are preferably prepared in water, conventionally mixed with a surface active agent, such as hydroxypropyl cellulose.

Depending on the specific conditions to be treated, such agents can be formulated and administered systemically or locally. In Remington's Pharmaceuticai Sciences, Ed. 18, Mack Publishing Co., Eaton PA (1990), techniques for formulation and administration are described. Suitable routes may include the oral, rectal, transdermal, vaginal, transmucosal or intestinal route and parenteral route, including subcutaneous intramuscular, intramedullary, as well as intratecal, intraventricular, intravenous, intravenous, intravenous, intravenous, intravenous, intravenous, intranasal or intraocular, to name just a few.

For injection, the agents of the present patent application may be formulated in the form of aqueous solutions, preferably in the form of physiologically compatible buffers, such as the Hanks solution, the Ringer solution, or a saline buffer solution. For transmucosal administration, penetrating agents suitable for the barrier to be permeated are used in formulations. Such penetrating agents are generally known in the art.

In soft gelatin capsules, the active compounds may be dissolved, or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Additional stabilizers can be added.

Biological activity

In vitro antibacterial evaluation

The compounds of the present patent application have been evaluated against numerous species (strains) of 3-lactam-resistant bacteria (eg, methicillin-resistant, vancomycin-resistant and / or ampicillin-resistant), by determining the minimum inhibitory concentration ( MIC, mg / ml) of each compound relative to each strain. The minimum inhibitory concentration, the lowest concentration of antibiotic, which inhibits the development of the tested organisms, was determined by the agar dilution method. To determine the minimum inhibitory concentration for bacterial isolation, the test compounds were incorporated in a series of dilutions twice in liquefied Mueller-Hinton agar. After solidification, a number of different bacterial species (strains) were inoculated using a reproductive medium on the agar surface. After overnight incubation, the breaking point of the minimum inhibitory concentration was determined to be the lowest drug concentration that completely inhibits development (growth) by neglecting a single colony or a weak fog. The procedures used in these studies

RO 119830 Β1 were standardized by the National Committee for Clinical Laboratory Standards (NCCLS - 1

National Committee for Clinical Laboratory Standards), as well as NCCLS publications entitled Methods for Dilution Antimicrobial Susceptibility Tests (1991), which is included here as a 3-point reference.

Aliquots of antimicrobial agents in phosphate buffered brine (PBS) 5 were prepared at a pH value of 7.2. Tween 20, or dimethylsulfoxide was used as the solubilizing vehicle as needed. Standard methods for vortexing, sonication, and gentle heating have been used to facilitate solubilization of the test agent. In general, the concentration of the stock solution was 10 times higher than that of the highest concentration of the drug tested. A 9 stock solution of 1.28 mg / ml was used at the highest working concentration of 128 µg / ml. Twice dilution in series was performed with a value less than or equal to 11 0.25 µg / ml. Each level of the drug was tested in duplicate. The drug was diluted twice in sterile 50 ml tubes with a final drug volume of 5 ml. After adding 45 ml of molten agar, a 10-fold dilution was obtained. In a 15x150 mm square Petri dish with grill two plates, 25 ml, were inserted and the Petri plate was allowed to harden.

A control plate with a reference drug, either cefotaxin, vancomycin or imipe-nem, was used as a positive developmental control. Stock concentrations of the reference antibiotics were prepared and frozen at -80'C. After preparation, the control plates were sealed and stored in the freezer for up to one week before use; however, imipenem control boards must be prepared just before use. All 21 test plates were used within 24 hours of preparation.

Satisfactory results were obtained where the inoculum contained approximately 104 23 cfu - colony forming units plus or minus 0.5 logs. Starting with pure cultures of the test on agar plates, a few isolated colonies were transferred into a tube with 25 nutrient solution and allowed to grow 4 ... 6 h at 35 ... 36 ° C to reach the log growth phase . The culture solution (medium) was added dropwise to PBS to achieve a standard turbidity of 0.5 0.5 McFarland equal to 108 cfu / ml. This was subsequently diluted 10 times in PBS to reach an inoculum working concentration of 107 cfu / ml. When applying 1 pl of 29 inoculum to the surface of the agar, a concentration of about 104 cfu / spot is obtained.

Sterile 1 μΙ loops are used to inoculate test plates with either isolate in a network provided on the agar plate. An alternative method of inoculation involves the use of a replica plate, a device with 48 steel needles allowing simultaneous inoculation of 33 multiple isolates. After the spots are dried, the plates are incubated at 35-36'C for 16-20 hours. The end points are evaluated as the minimum inhibitory concentration (MIC) of the anti-microbial agent.

The novel agents of the present invention are remarkable for their enhanced activity against S. Aureus Col. and Enterococci (E. faecium and E. faecalis). The species S. Aureus Col. is a high level PBP 2a producer, while S. Aureus Col. 8A, its isoenic partner 39, lacks PBP 2a.

Certain compounds have shown a broad spectrum of activity against both S. Aureus 41

Col. and S. Aureus Col. 8A, as well as against Enterococci. Species S. Aureus Col. 8A is highly selective for all test agents including control cefotaxim. Thus, the compounds of the present invention are effective against bacteria that produce PBP 2a. Certain compounds have been shown to be very active against Enterococci. Certain other compounds of the present invention are efficacious against E. coli in addition to gram-positive organisms.

RO 119830 Β1

Antibacterial evaluation in vivo

The compounds with superior activity in vitro, when compared with the reference antibiotics, are always evaluated in the murine model for lethal bacterial peritoneum.

Groups of female Swiss-webster mice (Simonsen, Gilroy, CA) were each challenged intraperitoneally (IP) with tenfold increases in bacterial inoculation. This allows the calculation of the average lethal dose (LD ₅₀ ) and LD100. For preliminary evaluation of a new antibiotic, the mice were challenged intraperitoneally with an LD ₁₀₀ bacterial titer. in two equal doses, administered during the bacterial challenge and two hours later, groups of ten mice were treated, each of them, subcutaneously with twice increments of the drug tested and an antibiotic of known efficacy in mice and humans (respectively , positive control). Mice were kept under observation for 72 hours. Those who remained alive after 72 hours were considered long-term survivors. The total dose of the drug in mg / kg that protects 50% of the mice in the group from death is called the average protective dose (PDjo). PD ₅₀ doses are similarly determined for different pathogens. The quantitative endpoints for the new drug are then compared with those obtained with the reference antibiotics.

16-fold dilutions of the inoculum in 0.5 ml of 7% sterilized pig gastric mucin (Sigma) are injected intraperitoneally in groups of 5 mice each. A control group of 5 mice received only mucin. The mice were kept under observation for 72 hours. Those who were found alive after 72 hours are considered long-term survivors. The mean lethal dose (LDjo) and 100% lethal dose (LD100) were determined by the respective test.

For antibiotic efficacy studies, mice were challenged intraperitoneally with bacterial titers leading to LP100 for the tested species. in two equal doses administered during bacterial challenge and two hours later groups of 10 mice each were treated subcutaneously (SC) with twice the antibiotic test increments; another group was treated similarly to a reference antibiotic of known efficacy in animals and humans. Dosages of the drug can range from 0.01 to 512 mg / kg. if the drug is poorly soluble, use Tween 20, or propylene glycol to solubilize the drug. The animals were kept under observation for 72 hours. The protective dose 50% (PD ₅₀ ) coincides with the effective dose 50% (ED ^) and the healing dose 50% (CD ^). Blood samples were cultured from the hearts of mice that survived on a brain-heart infusion agar. Animals that received a protective dose from the drug tested remained alive after 72 hours although they may appear to be somewhat ill or even very sick during the observation period. Infectious, placebo-treated control mice and those who received inefficient or lower doses of the tested drug, respectively, demonstrated a high mortality rate. Most of the mice died within 6 to 48 hours. Those who lived after 72 hours are considered long-term survivors.

RO 119830 Β1

Table 1

Antlmicroblene properties ale 7- (acylamldo)> 3- (arylthio) cefeiTi fîaesbm it 2 ά 4 6 S. "wrwATCC2WU "035 O.B "006 05 035 OB OAS £ gold <025 "ao6 TO / * 0l5 CJ5 <0.06 013 XmrartPCl (McttfKte *) t 0.5 05 025 $ 02 05 & owtut AICC tt709 (Metf) "WS - - 03 025 "0.06 "ao6 & «ErutCol (M '1h'XlKO 32 4 t 8 8 8 2 & ttrtitf 76 (McAtyta *) 32 8 4 8 8 16 8 X «unttt ATCC UJSMMctt *) 32 8 4 8 4 16 8 Sewri ^ Sj »in« 56 (MAV) 32 8 4 8 8 16 8 X. kdamâtyifcvd 0 $ 64 16 4 8 8 • 6 6 £ / high ATCC 29212 "OÎJ it 0.5 05 05 3 05 £ / «rfra ATCC 356« 4 2 1 2 2 4 2 £ joeeftnH V * nA. (Vaa *) 4 8 4 1 4 32 8 £ feecrfi * VmT & (V * »*) 0-5 4 02 1 4 4 8 £ fiudum A491 {AUfh > m > 32 > 32 > 32 > 32 > 32 > 32 £ ATCC2S992 cells <025 > 32 16 2 4 > 32 > 32 P ravownM ATCC 27453 1 > 32 > 32 > 32 > 32 > 32 > 32 ---- ffrțMfam ", _w Imfom » Z 2 2 12 them 21 £ «mmw ATCC 29213 "025 03 t 025 05 0.3 03 X. otMMtf Col8A (14iedt * XIuf) "025 02 1 013 05 1 05 HemndPCt (MrtflfW} "025 2 it J 05 1 05 £ ακηαα ATCCIW09 (Μβώ *) "025 I would 1 <0.06 05 05 0.25 £ CW quit 32 8 2 1 2 4 2 £ nwm 76 (ΜαΟ ^ χΐκΠ 32 8 4 4 3 8 2 £ mmui ATCC 335 »<McA) 32 B 4 4 2 4 2 £ with Spete m $ 4> [ΜΛ *) 32 8 4 4 2 8 2 £ & Nmc $ 4toa8 £ (M9t! £) 64 32 4 U 4 4 2 E-fau / Ba ATCC »212 "0.25 1 0.5 it 05 025 025 £ jtaM'ATCCMffi7 4 4 2 1 2 1 1 £ / ^ teatVanA (V "it ^ 4 16 8 4 4 4 4 Kj & ecdftxVaflBfVarf ¹ ) 05 2 I would 2 it 0.3 0.5 £ Jtacten A491 (AHJ? *) > 121 > 32 32 > 32 > 22 > 32 > 32 E coif ATOC25992 "025 4 2 > 32 4 B 8 ATCC27Î52 1 > 32 > 32 > 32 > 32 > 32 > 32 -QrgqjHa 15 11 15 IZ 18 £ arad ATCC »213 "023 2 05 1 025 0.25 1 S. attracted ColBAf & talOOac) 0) 25 3 05 1 025 0.5 1 £ atena PCI (M «h ^s XW) "025 2 05 1 025 025 1 S. airaa ATCC 15TC9 "025 2 025 4.5 013 025 1 £ SircM Col (MtdPXkur) 32 4 4 4 0.5 2 44 £ arw76 (Mah * Xtee ') 32 8 4 4 1 4 8 5. atewATCC $ 3-5 XMcth) 32 8 2 4 1 2 4 $. araa Spoln # 2% (Meft *) 32 8 4 4 1 4 8 X fvtmotyiicus C5 (MdtP) 64 B 4 8 2 8 8 E / »the» «tATCC292t2 ίϋ.25 I 025 2 <0.06 0.13 025 Ejdectan ATCC 33467 4 4 1 2 05 it 2 E jâectan VanA (V «n. ·) 4 8 2 4 0.25 021 2 E.Jhtcalhr'Vtt ^ (¥ * «*) 05 2 015 0-5 0'3 0.5 05 £ / ιμ4 «μΑ491 (ΑκζΛ) > 128 > 31 > 32 > 32 8 > » > 32 £ ro »ATCC25992 "023 ft 4 8 S 2 8 P. atntgbum ATCC 27453 1 > 32 > 32 > 32 > 32 > 32 > 32

RO 119830 Β1

Table 1 (continued)

Antimicrobial properties 7- (acllaniidg) -3- (ariltÎj) cefem

Orpanh » bnjftKwn «025 LD 0.5 2 R 0.3 21 025 22 0.25 2. 3 1 them 1 Saawx ATCC 29213 5 £ arnux ColâAiMcCi'yiac] "025 QJ 0.3 025 05 05 1 £ mnnir 20 <045 05 0.5 85 it 05 t $ asrw ATCC 13209 Oteih ¹ ] <025 04 0.3 1 t 05 1 7 £ atftw Cot núMach ^t ) (tac ') 32 8 2 I 2 2 8 £ amur 76 (Meth'Xlac'J 32 8 4 1 2 4 8 £ struck ATCC ZttKțMeth ' ¹ ) 22 8 2 1 2 4 4 9 £ awvw Spafa 1356 {Meth *) 32 8 4 1 2 4 4 £ hoemefyifcta OS (Medium *) 64 16 4 2 2 4 8 £ _ / & μο1Ϊ »ATCC 29212 "025 I 1 o.tl 0.13 05 0.25 11 ATOC 35667 4 1 it 0.5 1 2 2 £ jaeeiuiH VanA (Van *) 4 2 and 1 2 4 4 E / heciflKs V «aS (Vaa *) 04 05 05 013 03 1 05 13 ejtafcMAOliAlPp'j > 125 > 32 > 32 â 16 > 32 > 32 £ eettATCC23992 <0.25 8 4 32 8 2 8 15 P. OiwiniOâ ATCC27S53 ¹ 1 > 32 > 32 > 32 > 32 > 31 > 32 Qrnntan Ixilpeneni 2. 3 Ά IZ of 22 £ tww ATCC 29213 "0.25 4.25 0.11 023 t 023 045 17 £ oamtt Οθ1 & Α (Μβώ * ΧΙΐ £ 1 sO.25 023 013 013 025 025 013 £ owwPCl (Meltf) (heel *) "025 025 0 (3 025 03 $ 02 "025 £ amur ATCC î ¥ K »(Meft *) <025 8.23 <0.46 0.13 013 01J <02 $ and y £ amur Cal (Mah ^ Xlaf) 32 1 03 05 z 1 "4 £ amur Η (Mcth * Xl »c *) n 2 1 1 2 1 2 £ amur ATCC 33 »3 <Mtffc *) 32 1 1 1 4 2 1 Z 1 £ amur Rear # 336 (Meth *) 32 2 1 1 2 2 1 £ hmofytiaa 03 (Mad ^) 64 2 2 2 4 -2 1 no £> MfeATCCini2 <025 013 "0.06 - < ". 06 0. " "006 "006 zo £ / 2 »cJtaw ATCC 35667 4 ! 025 025 1 025 03 H / irei® · »VaaA (V <a *) 4 2 03 44 4 03 1 £ ^ eMKrVMB <Vu ^k > 03 013 013 <006 025 <006 <4.06 zu £ jEieefa »A49I (Atnp *) > 121 32 8 4 16 4 8 £ "JfATCC25992 "025 4 > 32 8 2 8 8 27 P. atttiehtMa ATOC 27853 it > 12 > 32 32 32 > 11 > 32 .Qfţmuisw lmioenem IX 31 32 you £ 2 zy £ amur ATOC 29213 <025 023 0.25 045 <0.06 ws 05 £ amur CalgAtMeth ^ Mf) <025 023 MAN 0.25 <006 025 .023 £ amur PCI (Mrth * XI «c9 <023 023 05 0.25 013 04 025 £ amur ATCC 13709 CMeft®) <025 025 0.13 013 <006 $ 02 025 IOC burger (McA '^ noodle 32 2 it 1 it 2 1 33 £ ei »™ 76 (Meth ^ Xlac ') 32 2 2 1 1 2 2 £ aurtur ATCC 33593 ^^} 32 2 2 2 1 2 1 S.atma Spaiaf 56 (Muth ') 32 3 2 1 1 2 1 35 S taemeiyâctaOS (M «h ^K ) 64 4 4 2 1 4 2 Epocalii ATCC 29212 <025 6.5 <0.06 0.13 <0.06 <006 0.25 ATCC 35667 4 04 03 4.3 023 $ 02 45 37 E, fiocim VmA (Vmi *) 4 1 1 2 04 1 £. Jâecdâ V «oB (Van *) BONE $ 02 013 013 <006 025 0.13 £ fctKium A491 (AmpP) > 123 8 8 8 4 4 8 39 £ «rf <ATCC25m iOJM 8 8 1 4 8 16 P. amtfinasa ATOC 27353 1 > 32 > 32 32 > 32 > 32 > 32

RO 119830 Β1

Table 1 (content)

The antimlcrobial properties of 7 -facllamldo) -3- (ariltio) Otysnlstn (iplptţpeiB 3Z 38 32 41 42 Xtwfcur ATCC 29213 <0.25 0.5 013 025 025 013 0.13 £ cuuvitf CoMA (Me (b * Klur) <013 <9.06 0.13 05 02 025 015 <025 1 025 05 0.13 025 0.13 S.rnmu ATCC13709 (Meth ») <025 <9O6 o.n 025 0.25 013 013 5 tnrvurCol 32 0.5 > 2 2 I 05 S. «Μ, βΜΓ 76 32 4' 1 4 2 1 1 A «w ATCC 3îSM (Mcth) 32 16 1 4 2 1 1 £ «racrfyain 9156 (M« th *) 32 9 1 4 2 and t £ homofytiaa 05 (Mcth *) 64 8 2 t 4 1 2 f / xoiiir ATCC 29212 <015 0.25 0.13 025 0.13 <006 <0.06 £ _ & * dMiAT0C3M67 4 0.5 1 1 it 025 CL25 £ fiudOM V «ttA (Via *) 4 2 2 2 2 it 05 Efatadis VanB (VmA) 05 03 0.13 025 025 <M6 <006 £ / mcîumA49I (ΑΛρ *) > 122 > 32 > 32 32 W 6 4 £ cdf ATCOSWl 4025 > 32 2 S 8 4 2 r.amrrinao ATOC21U3 1 > 32 > 32 > 32 > 32 12 12 Oroiritri ImhweBi be be be be £. M £ aunw ATCC 29213 <025 03 05 1 t t 03 £ w * at C «l8A (Metl | ^t XltC ') <025 05 05 1 05 05 05 £ oioiexrPCl (MiO ^ lia ⁴ ) <025 1 2 2 2 2 05 Done ATCC M709 (Met6 ') <025 05 2 2 2 2 O2J £ ourttttr Cot (Medium * Xteir) 32 3 4 4 2 2 4 £ «wutf 76 (MetPKh» ⁴ ) 32 2 4 4 4 2 8 £ «MtottATCC Î3S53 (MeeA) 32 2 4 4 3 2 4 £ anut Spila ItiSA U 2 4 4 4 2 8 £ famwbiitaB 05 (MeOi *) 64 4 8 & 8 4 16 EfotatlU ATCC29212 <025 0.13 013 0.13 of » 053 025 £ jSNd »ATCC 35667 4 1 4 2 2 2 1 £ fotth »· VuAtVoF) 4 1 2 4 2 1 4 Sfaab VmB <Vm * Î 0.5 025 • w · - - - 05 Efixcltuu A49S (AsțA) > 12 » t 1" 16 H 16 32 £ m # AT0C25992 3 8 16 0 8 4 ATGC 27tS2 > » > 32 > V> > » > 23 > 12 tn-puus »...... jmiirt "Nope JS » you 22. 3S SS 'S4 Sowvitf ATCC 29213 <025 025 0.13 025 03 05 025 & mus ΟΗΒΑ (ΜβΛ * χΐικ: ') <025 05 025 0.5 025 0.5 025 £ awewFCl (Mcthftîăcr) <025 03 0.25 0.5 0.5 1 025 £ «no» ATCC 13709 (McA *) <025 825 0.13 05 03 025 025 £ «rule Col (Μοώ * Χ» »Π 32 2 2 2 2 4 2 & awnir74 (M «h *) (l« r) 32 2 2 IT 2 4 2 £ «hw ATCC 33593 (Meih *) 32 2 2 2 2 2 1 5 amut SiMdn .0356 (Mcth *) 32 2 2 2 2 4 2 £ haeaiafyitatrCi (Methyl *) 64 4 4 2 2 4 2 E / ăeeeiii ATCC 29112 <0.25 0.Π 0.13 0 (3 <006 013 0.13 £ Jfccini> ATCC 35667 4 1 1 0.13 <006 1 05 Efircom VtniA (Vin *) 4 2 2 it | 2 1 £> t "aitrVanB (Vat ^) 01 0.13 05 025 W 0.25 025 £ faeciwn A491 (Arap) > 12 ' 16 16 » 4 16 8 £ ctAATCCK992 <AI5 0 4 S 2 4 8 f. atngiMM ATCC 27853 1 > 32 > 32 > 32 > 32 > 32 > 32

RO 119830 Β1

Table 1 (continued)

The antimlcroblene properties of 7- (acilarnfclo) -3- (arlltiQ) cefem

Orranfciff Imipenetn 55 £ 5 52 58 59 5Q 025 £ awvHt ATCC 29213 n0.25 0.5 05 1 04 05 £ aurttu CoteAțMfltfXIao ^ <0.25 0.5 03 1 05 0.25 015 Silly PCI (Meth'Xtac *) <0223 1 03 1 1 03 025 £ Auma ATCC13709 (Metif) s0_25 023 023 "4 05 0.13 0.13 3. ww ΟοΙ (ΜεΟι *) (1ΐ € θ 32 4 2 4 4 2 2 S. attrmt 76 (Mcth'Xtoc ') 32 4 2 4 4 2 1 £ minute ATCC 33593 (M «h *) 32 2 2 4 2 2 2 £ aurai »Spain # 356 (Mcîh *} 32 4 2 4 4 4 2 £ toeiwuțcicMrttS (Moh *) 04 4 4 of 4 4 4 AfiteatlU ATCC 29212 £ 025 0.25 0.13 0.13 05 03 03 E.faechtnXICCMtfl 4 0.5 1 1 1 1 1 Ε, ^ κίυιι VonA (Vsn ¹ ) 4 2 1 2 2 2 2 Efatcaiis Van9 (V «A *) 03 03 2 4 05 04 025 Efatâua A491 iAnțfP) > I2B 16 of 16 16 16 16 ATCC25992 <0l25 & s 4 of 8 of f _r Otng * aaa ATCC27B5J 1 > 52 > 32 > 32 > 32 > 32 _OfTOtlknl iMtoPIICTl £ 1 S2 63 SL you £ ATCC 292t3 license s »45 I a.5 025 0Λ5 03 £ rame CottAfMotfOttO $ Λ2 ι 0.5 0.13 & 2S 05 £ ouraut? Cl (M «h ^s XIâ« f *) $ t & 2 1 03 023 0.5 1 3 mma ATCC t »M * 62.5 1 0.5 023 025 04 i ttunaa Col (Mcth ^ Xlaf) 32 4 4 2 3 2 X aiMif 76 (Mcth'Xtoc ^ 32 4 4 2 4 4 £ rarely A.TCC33393 (Mctfe) 32 4 4 2 2 4 £ wuu fynfa * 356 (McOi *) 32 4 4 4 4 4 £ taBMgrtfcieOS (McCh *) 64 of 4 2 4 4 Expired ATCC 29212 £ 0.25 015 0.13 0.11 045 0.25 £ jtecfent ATCC 35661 4 t 1 03 t - E. jâedtm VeaA (Ve «P) 4 2 2 1 2 2 EfiMcalis VmB (Van *) 0.5 0-75 .25 ¢ Olm .5 ¢ 05 Efiitefrm A491 (Amp *) H24 16 16 16 16 1" E.cali ATOC25W2 <015 16 of 16 of 16 P.ttengimaa KKCW653 1 > 32 > 32 > 32 > 32 > 33

Compound: survivors vancomycin imipenem 1 2 10 Dose: 10 mg / kg 10/10 5 mg / kg 10/10 2.5 mg / kg 4/10 10/10 9/10 1,25 sqm / sq 2/10 8/10 7/10 10/10 0.625 mg / kg 2/10 10/10 6/10 8/10 8/10 0.3125 mg / kg 10/10 5/10 5/10 2/10 0.156 mg / kg 10/10 2/10 0/10 2/10 0.078 mg / kg 6/10 2/10 0.039 mg / kg 3/10 1.29 ^ED (mg / kg) 1.94 0.06 0.39 0.42

RO 119830 Β1

Compound: survivors 11 14 15 16 17 Dose: 40 mg / kg 20 mg / kg 10 mg / kg 5 mg / kg 10/10 5/10 6/10 2.5 mg / kg 6/10 9/10 5/10 8/10 3/10 1.25 mg / kg 5/10 3/10 2/10 5/9 5/10 0.625 mg / kg 3/10 3/10 0/10 3/10 2/10 0.3125 mg / kg 1/10 1/10 2/10 1/10 2/10 0.156 mg / kg 1/10 2/10 EDgn (mg / kg) 0.96 1.13 4.63 1.00 3.59

Compound: survivors 18 26 27 28 29 Dose: 5 mg / kg 6/10 9/10 7/10 7/10 7/10 2.5 mg / kg 2/10 7/10 6/10 3/10 9/10 1.25 mg / kg 2/10 5/10 2/10 4/10 9/10 0.625 mg / kg 2/10 5/10 0/10 1/10 5/10 0.3125 mg / kg 3/10 1/10 0/10 1/10 2/10 EDgo (mg / kg) 4.44 1.06 2.64 3.01 1.26

Compound: survivors 30 32 33 39 56 Dose: 5 mg / kg 10/10 8/10 8/10 10/10 8/10 2.5 mg / kg 10/10 5/10 9/10 6/10 8/10 1.25 mg / kg 4/10 5/10 5/10 6/10 3/10 0.625 mg / kg 2/10 1/10 4/10 3/10 3/10 0.3125 mg / kg 0/10 0/10 0/10 1/10 2/10 ED _B0 (mg / kg) 1.14 2.00 1.19 1.15 1.23

Compound: survivors 57 58 59 64 65 Dose: 5 mg / kg 9/10 5/10 10/10 8/10 8/10 2.5 mg / kg 5/10 5/10 4/10 4/10 3/10 1.25 mg / kg 4/10 2/10 4/10 4/10 1/10 0.625 mg / kg 4/10 1/10 6/10 1/10 2/10 0.3125 mg / kg 4/10 1/10 4/10 1/10 1/10 ED50 (mg / kg) 1.08 4.10 0.81 2.27 3.10

Compound 1. Trifluoroacetic acid salt of (7R) -7- [(phenylacetyl) amino] -3- (3-isothio-ureidomethylpyrr-4-ylthio) -3-cefem-4-carboxylic acid 47 Compound 2 The trifluoroacetic acid salt of (7R) -7 - [(phenylacetyl) am- no] -3- (4-isothio-ureidomethyl-1,2,3-thiadiazol-5-ylthio) -3-cefem-4- 49 carboxylic acid

RO 119830 Β1

Compound 3

Compound 4

Compound 5

Compound 6

Compound 7

Compound 8

Compound 9

Compound 10

Compound 11

Compound 12

Compound 13

Compound 14

Compound 15

Compound 16

Compound 17

Compound 18

Compound 19

Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (aminothiazol4-yl) -2- (hydroxy-imino) acetamido] -3- (3-isothiouridomethylpyrid-4-yl) -3-cefem-4 carboxylic

(7R) -7 - [(Z) -2- (aminothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- (4-isothiouridomethyl) acid trifluoroacetic acid salt.

1,2,3-thiadiazol-5-ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(phenylacetyl) amino] -3- (4-isothio-ureidomethylthiazol-5-yl) -3-cefem-4-carboxylic acid salt with trifluoroacetic acid

(7R) -7 - [(phenylacetyl) amino] -3- [4- (3-pyrrolidino-thiomethyl) -1,2,3-thiadiazol-5-ylthio] -3-cefem-4-carboxylic acid salt with trifluoroacetic acid

Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (aminothiazol4-yl) -2- (hydroxy-imino) acetamido] -3- (4-isothiouridomethylthiazol-5-yl) -3-cefem-4 carboxylic

(7R) -7 - [(Z) -2- (aminothiazole-4-yl) -2- (cyclo-pentyloxyimino) acetamido] -3- (3-isothiouridomethylpyrid-4-yl-thio) acid trifluoroacetic acid salt. -3-cephem-4-carboxylic acid

Trifluoroacetic acid salt of (7R) -7 - [(phenylacetyl) amino] -3- (3-aminoethyl-thiomethylpyrid-4-ylthio) -3-cefem-4-carboxylic acid

(7R) -7 - [(Z) -2- (aminothiazole-4-yl) -2- (hydroxy-imino) acetamido] -3- (3-aminoethylthiomethylpyrid-4-thio) -3-cefem acid trifluoroacetic acid salt 4-carboxylic acid

Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (aminothiazole -4-yl) -2- (hydroxy-imino) acetamido] -3 - [(methylaminoethylaminoethylthiomethyl) -1,2,3- thiadiazol-5-ylthio] -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (aminothiazole-4-yl) -2- (hydroxy-imino) acetamido] -3 - [(guanidinoethylaminoethylthiomethyl) -1,2,3- trifluoroacetic acid salt. thiadiazol-5-ylthio] -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (aminothiazole-4-yl) -2- (cyclo-pentyloxyimino) acetamido] -3- (3-aminoethylthiomethylpyrid-4-yl) -3-trifluoroacetic acid salt cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (aminothiazole-4-yl) -2- (hydroxy-imino) acetamido] -3- (3-guanidinoethylthiomethylpyrid-4-yl) -3-cefem acid trifluoroacetic acid salt 4-carboxylic acid

(7R) -7 - [(Z) -2- (aminothiazole-4-yl) -2- (hydroxy-imino) acetamido] -3- (3-methylaminoethylthiomethylpyrid4-yl) -3-cefem acid trifluoroacetic acid salt 4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- (3-aminoethylthiomethylpyrid-4-ylthio) acid trifluoroacetic acid salt '3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (aminothiazol4-yl) -2- (hydroxy-imino) acetamido] -3- [3- (3-pyrrolidinothiomethyl) pyrid-4-ylyl] trifluoroacetic acid salt 3-cephem-4-carboxylic acid

Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (aminothiazol4-yl) -2- (hydroxyimino) -acetamido] -3- [3- (N-methyl-glycyl) aminoethylthiomethyl-pyrid- 4-ylthio] -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (aminothiazol4-yl) -2- (hydroxyimino) -acetamido] -3- [3- (2-amino-1,1-di-methyl) trifluoroacetic acid salt letiltio-methyl) pyrid-4-ylthio] -3-cephem-4-carboxylic acid

RO 119830 Β1

Compound 20

Compound 21

Compound 22

Compound 23

Compound 24

Compound 25

Compound 26

Compound 27

Compound 28

Compound 29

Compound 30

Compound 31

Compound 32

Compound 33

Compound 34

Compound 35

[7R] -7 - [(Z) -2- (aminothiazole-1) trifluoroacetic acid salt

4-yl) -2- (hydroxyimino) acetamido] -3- (3-aminoetiltiopirid-4-ylthio) -3-cephem-4-carboxilic3

(7R) -7 - [(Z) -2- (2-amino-5-bromothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- (3-aminoethylthio-5-methylpyridic acid trifluoroacetic acid salt -4-ylthio) -3-cephem-4-carboxylic acid

Trifluoroacetic acid salt of (7R) -7- [(Z) -2- (2-amino-5-7 chlorothiazol-4-yl) -2- (hydroxyimino) acetamido] -3 - [(methylaminoethylaminoethylthiomethylO-I ^) S-thiadiazol-B-ylthio-S-cefern-carboxylic acid 9

Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (2-fluoroethoxy-imino) acetamido] -3- (3-aminoethylthiomethyl-11-pyrid -4-ylthio) -3-cephem-4-carboxylic acid

Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothia-13 zol-4-yl) -2- (hydroxyimino) -acetamido] -3- (3- (glycyl) aminoethylthiomethipyrid -4-ylthio) -3-cefem-4-carboxylic acid 15

(7R) -7 - [(Z) -2- (aminothiazol4-yl) -2- (hydroxyimino) -acetamido] -3- (3- (N-formylamidoyl) aminoethyl-17 thio-methylpyridic acid trifluoroacetic acid salt -4-ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2-phenyl-2- (hi-19 droxyimino) acetamido] -3- (3-aminoethylthiomethylpyrid-4-ylthio) -3-cefem4-carboxylic acid salt with trifluoroacetic acid 21

(7R) -7- [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- [3- (3-aminopropyl) acid trifluoroacetic acid salt ) 23 thio-methylpyrid-4-ylthio) -3-cefem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5- 25 chlorothiazol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3 - [(methylaminoethylaminoethylthiomethyl) acid trifluoroacetic acid salt -1,2,3-thiadiazol-5-ylthio] -3-cefem-4-carboxylic 27

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- [3- (glycyl) aminoethyl acid salt with trifluoroacetic acid - 29 aminoethylthiomethylpyrid-4-ylthio] -3-cefem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5- 31 chlorothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- [3-aminoethylthiopyrid4 acid trifluoroacetic acid salt ynylthio] -3-cephem-4-carboxilic33

Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-arnino-5-chlorothiazol-4-yl) -2- (hydroxy-imin0) acetamido] -3- (3- (N-formamides) - 35-nyl) -aminoethylthiomethylpyrid-4-ylthio] -3-cefem-4-carboxylic acid

Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5- 37 chlorothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- [3- ( 2hidroxiporp 3-amino-1-ylthiomethyl) pyrid-4-ylthio] -3-cephem-4-carboxilic39

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3- (3-aminoethyl-41-thiomethylpyridic acid trifluoroacetic acid salt -4-ylthio) -3-cephem-4-carboxylic acid

Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5- 43 chlorothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- (3- (3- N-formamidoilaminopropiltiometilpirid-4-ylthio] -3-cephem-4-carboxilic45

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- [3- (glycyl) amino acid trifluoroacetic acid salt - 47 propyl-thiomethylpyrid-4-ylthio] -3-cefem-4-carboxylic acid

RO 119830 Β1

Compound 36

Compound 37

Compound 38

Compound 39

Compound 40

Compound 41

Compound 42

Compound 43

Compound 44

Compound 45

Compound 46

Compound 47

Compound 48

Compound 49

Compound 50

Compound 51

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- (3- (2-aminopropic acid) trifluoroacetic acid salt -1iltiometil) pyrid-4-ylthio) -3-cephem-4-carboxylic acid

Trifluoroacetic acid salt of (7R) -7 - [(phenylacetyl) amino] 3- (4- (2-aminoethylthiomethyl) -1 ^ .S-thiadiazole-S-ylthio-S-cefem-acarboxylic acid

(7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) -acetamido] -3- (4- (2-aminoethylthiomethyl) - acid trifluoroacetic acid salt

1,2,3-thiadiazol-5-ylthio) -3-cephem-4-carboxylic acid

Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- (3-carboxamidomethyl-methylpyrid-) salt 4-ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxyimino) -acetamido] -3- (3- (2-aminoethoxymethyl) acid trifluoroacetic acid salt pyrid-4-ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- (3- (2-N) trifluoroacetic acid salt -metilaminoetiltio-methyl) pyrid-4-ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- (3- (pyrrolidin-3-ylthiomethyl) acid trifluoroacetic acid salt ) pyrid-4-ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- [3- (N-methylglycyl) acid trifluoroacetic acid salt ) tiometilpirid-aminoethyl-4-ylthio] -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- (3- (5-aminopentyloxymethyl) pyridine acid trifluoroacetic acid salt -4-ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- (3-aminoethylsulfonylmethylpyrid-4-) trifluoroacetic acid salt. ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- (3- (4-aminobutoxymethyl) acid trifluoroacetic acid salt ) pyrid-4-ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- (3- (3-aminopropyloxymethyl) acid trifluoroacetic acid salt ) pyrid-4-ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxyimino) -acetamido] -3- (3- (4-amino-) trifluoroacetic acid salt 2-butyn-1-yl) pyrid-4-ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- (3- (2-aminopropyloxymethyl) - acid trifluoroacetic acid salt pyrid-4-ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- (3- (4-amino) acid trifluoroacetic acid salt -2-Zbuten-1-yl) pyrid-4-ylthio) -3-cephem-4-carboxylic acid

(7R) -7- [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxy-imino) acetamido} -3- (3- (3-aminopropylthio) acid trifluoroacetic acid salt ) pyrid-4-ylthio) -3-cephem-4-carboxylic acid

RO 119830 Β1

Compound 52

Compound 53

Compound 54

Compound 55

Compound 56

Compound 57

Compound 58

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- (3- (piperidin-4) trifluoroacetic acid salt -iltiometil) pyrid-4-ylthio) -3-cephem-4-carboxylic acid

Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- (3-aminoethylsulfinylmethyl-pyrid-) salt 4-ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- (3- (N-acetylamidinooyl) salt with trifluoroacetic acid salt ) -aminoetiltiometiipirid-4-ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- (3- (5S-5) trifluoroacetic acid salt N, N-dimethyl-carboxamidopirolidin-3-ylthiomethyl) pyrid-4-ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- [3- (2RS-2) trifluoroacetic acid salt amino-3-hydroxy-prop-1-ylthiomethyl) pyrid-4-ylthio] -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- (3- (N-methylaminoethylamino) acid trifluoroacetic acid salt -etiltiometil) pyrid-4-ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- (3- (2R-2) trifluoroacetic acid salt N, N-dimethyl-carboxamido-2-aminoetiltiometil) pyrid-4-ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- (3- (2R-2) trifluoroacetic acid salt aminoetiltiometil-2-carboxamido) pyridin-4-ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- (3-isothiouridomethylpyrid-4-) trifluoroacetic acid salt. ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxyimino) -acetamido] -3- (3- (N, N-) trifluoroacetic acid salt dimetilcarboxamidometil-aminoetiltiometil) pyrid-4-ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxyimino) -acetamido] -3- (3- (2-amino-) trifluoroacetic acid salt 2-methylpropylthio-methyl) pyrid-4-ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- (3- (Nformylaminoethyl-thiomethyl) pyridine acid trifluoroacetic acid salt -4-ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- (3- (N-formylaminoethylthio) acid trifluoroacetic acid salt ) pyrid-4-ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(2) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxy-imino) acetamido] -3- [3- (2R-2) trifluoroacetic acid salt -amino-3hydroxyprop-1-ylthiomethyl) pyrid-4-ylthio] -3-cefem-4-carboxylic acid (Numbers of compounds with those of the tables with minimum inhibitory concentration (MIC): data reported for comparison with S. aureus strain ATCC 13709 sensitive to methicillin.)

Compound 59

Compound 60

Compound 61

Compound 62

Compound 63

Compound 64

Compound 65

RO 119830 Β1

Compound: survivors vancomycin imipenem 1 2 10 Dose: 10 mg / kg 10/10 5 mg / kg 10/10 2.5 mg / kg 4/10 10/10 9/10 1.25 mg / kg 2/10 8/10 7/10 10/10 0.625 mg / kg 2/10 10/10 6/10 8/10 8/10 0.3125 mg / kg 10/10 5/10 5/10 2/10 0.156 mg / kg 10/10 2/10 0/10 2/10 0.078 mg / kg 6/10 2/10 0.039 mg / kg 3/10 1.29 ED ₅₀ (mg / kg) 1.94 0.06 0.39 0.42

Compound: survivors 11 14 15 16 17 Dose: 40 mg / kg 20 mg / kg 10 mg / kg 5 mg / kg 10/10 5/10 6/10 2.5 mg / kg 6/10 9/10 5/10 8/10 3/10 1.25 mg / kg 5/10 3/10 2/10 5/9 5/10 0.625 mg / kg 3/10 3/10 0/10 3/10 2/10 0.3125 mg / kg 1/10 1/10 2/10 1/10 2/10 0.156 mg / kg 1/10 2/10 ED ^ (mg / kg) 0.96 1.13 4.63 1.00 3.59

Compound: survivors 18 26 27 28 29 Dose: 5 mg / kg 6/10 9/10 7/10 7/10 7/10 2.5 mg / kg 2/10 7/10 6/10 3/10 9/10 1.25 mg / kg 2/10 5/10 2/10 4/10 9/10 0.625 mg / kg 2/10 5/10 0/10 1/10 5/10 0.3125 mg / kg 3/10 1/10 0/10 1/10 2/10 EDjo (mg / kg) 4.44 1.06 2.64 3.01 1.26

Compound: survivors 30 32 33 39 56 Dose: 5 mg / kg 10/10 8/10 8/10 10/10 8/10 2.5 mg / kg 10/10 5/10 9/10 6/10 8/10 1.25 mg / kg 4/10 5/10 5/10 6/10 3/10 0.625 mg / kg 2/10 1/10 4/10 3/10 3/10 0.3125 mg / kg 0/10 0/10 0/10 1/10 2/10 ED., 0 (mg / kg) 1.14 2.00 1.19 1.15 1.23

RO 119830 Β1

Compound: survivors 57 58 59 64 65 Dose: 5 mg / kg 9/10 5/10 10/10 8/10 8/10 2.5 mg / kg 5/10 5/10 4/10 4/10 3/10 1.25 mg / kg 4/10 2/10 4/10 4/10 1/10 0.625 mg / kg 4/10 1/10 6/10 1/10 2/10 0.3125 mg / kg 4/10 1/10 4/10 1/10 1/10 ED ₅₀ (mg / kg) 1.08 4.10 0.81 2.27 3.10

Exemple11

The present invention will hereinafter be described by specific examples, but which should not be considered as limiting to the scope of the invention.13

Example 1. (7R) -7 - [(phenylacetyl) amino- [3- (4-hydroxymethyl-1,2,3-thiadiazol-5-ylthio) -3-cefem-4-carboxylic acid 4-methoxybenzyl ester15

To a stirred solution of 1,3-dichloroacetone (6.85 g, 54 mmol) and ethyl 3-mercaptopropionate (13.9 ml, 108 mmol) in anhydrous tetrahydrofuran (150 ml), triethylamine 17 is added dropwise. (15.0 ml, 108 mmol) at O'C and stirred at room temperature for 24 h. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The ethyl acetate phase is washed with 19% hydrochloric acid 5% and then with brine, dried over sodium sulfate and concentrated to dryness to give 17.4 g of 1,3-b / s - [(2- ethoxycarbonylethyl) thio)] crude acetone. A solution of 1,3-bis [(2- 21 ethoxycarbonylethyl) thio] acetone (6.22 g, 19.3 mmol), ethyl carbazate (2.40 g, 23.1 mmol) and a catalytic amount of acid p-toluenesulfonic acid in anhydrous acetonitrile (50 ml) containing molecular sieve 23 is stirred for 2 days at room temperature. The reaction is quenched with water / ethyl acetate and filtered. The filtrate is extracted with ethyl acetate. The organic extract was washed with aqueous sodium bicarbonate, dried over sodium sulfate and concentrated. The residue is triturated with hexane to afford 7.2 g of ethoxycarbonylhydrazone 1,3-b / s [(2-ethoxycarbonylethyl) thio] acetone. 27 ¹ H-NMR (CDCl ₃ ) δ: 2.2-2.4 (m, 9H), 2.6-2.8 (m, 8H), 3.42 (s, 2H), 3.54 ( s, 2H), 4.1-4.3 (m, 6H), 8.82 (wide s, 1H). 29

To a solution of hydrazone (7.2 g, 17.6 mmol) in 1,2-dichloroethane (20 ml) was added thionyl chloride (3.9 ml, 53 mmol) at 0 ° C and stirred overnight at room's temperature. The mixture 31 was concentrated to a volume of 10 ml, diluted with dichloromethane, washed with aqueous sodium bicarbonate, dried over sodium sulfate and then concentrated to dryness to give 6.47 g 33 of 5 - [( 2-ethoxycarbonylethyl) thio] -4 - [(2-ethoxycarbonylethyl) thiomethyl] -1,2,3-thiadiazole.

H-NMR (CDCl ₃ ) δ: 1.2-1.3 (m, 6H), 2.60 (t, 2H, J = 7), 2.68 (t, 2H, J = 7), 2 , 77 (t, 2H, J = 7), 35 3.24 (t, 2H, J = 7), 4.07 (s, 2H), 4.1-4.2 (m, 4H).

To a solution of 5 - [(2-ethoxycarbonylethyl) thio] -4 - [(2-ethoxycarbonylethyl) thiomethyl] -1,2,3-thiadiazole 37 (1.0 g, 3.0 mmol) in dichloromethane (40 ml ) is added, in several portions, to 0'0, m-chloroperoxybenzoic acid, until the disappearance of the raw material. The mixture was then washed sequentially with saturated aqueous sodium thiosulphate 39, 1% solution of cold sodium hydroxide and brine and concentrated to dryness. The oxidized product is treated with trifluoroacetic anhydride (2 ml) for 30 minutes at room temperature. After removal of trifluoroacetic anhydride under reduced pressure, the mixture was stirred in 1% ethyl acetate / sodium hydroxide (30 ml / 30 ml) for 30 min. The 43 ethyl acetate layer is concentrated to a volume of 5 ml and methanol (10 ml) is added. Sodium borohydride in excess (200 mg) is added portionwise, with O'C. After 30 min, the reaction was quenched by dilution with hydrochloric acid. The mixture was extracted with ethyl acetate and concentrated. The residue was purified by silica gel chromatography (1% methanol / dichloromethane) to give 225 mg 47 of 5 - [(2-ethoxycarbonylethyl) thio] -4-hydroxymethyl-12,3-thiadiazole.

Β1 EN 119 830 ^1H-NMR _(CDCl3) δ: 1.27 (t, 3H, J = 8), 2.71 (t, 2H, J = 7), 3.27 (t, 2H, J = 7 ), 4.16 (q, 2H, J = 8),

5.03 (s, 2H).

To a solution of 5 - [(2-ethoxycarbonylethyl) thio] -4-hydroxymethyl-1,2,3-thiadiazole (225 mg, 0.91 mmol) in anhydrous ethanol (20 ml), add sodium methoxide 0.5 M in methanol (1.6 ml). After 10 min, the mixture is concentrated and triturated with dichloromethane to give sodium thiolate. A solution of sodium thiolate and 4-methoxybenzyl ester (7R) -7 - [(phenylacetyl) amino] -3-trifluoromethanesulfonyloxy-3-cefem-4-carboxylic acid (500 mg, 0.85 mmol) in tetrahydrofuran ( 10 ml) was stirred at 0 ° C for 30 minutes and water (50 ml) was added. The reaction mixture was extracted with ethyl acetate and concentrated. The residue is purified by silica gel chromatography (2% methanol / dichloromethane) to give 407 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ: 3.22 (d, 1H, J = 18), 3.46 (d, 1H, J = 18), 3.61 (d, 1H, J = 16), 3 , 67 (d, 1H, J = 16), 3.81 (s, 3H), 4.95 (d, 1H, J = 5), 5.02 (s, 2H), 5.23 (d, 1H) , J = 12), 5.28 (d, 1H, J = 12), 5.83 (dd, 1H, J = 5.8), 6.14 (d, 1H, J = 8), 6.86 (d; 2H, J = 9), 7.2-7.4 (m, 7H).

Example 2. (7R) -7 - [(phenylacetyl) amino] -3- (4-chloromethyl-1,2,3-thiadiazole-5-ylthio) -3-cefem-4-carboxylic acid 4-methoxybenzyl ester

Thionyl chloride (85 ml, 1.71 mmol) is added to DMF (5 ml) and stirred for 30 minutes at room temperature. Add a solution of (7R) 7 - [(phenylacetyl) amino] -3- (4-hydroxymethyl-1,2,3-thiadiazol-5-ylthio) -3-cefem-4-carboxylic acid 4-methoxybenzylic ester , (400 mg, 0.684 mmol) in DMF (1 ml) and stirred for a further 30 min. The reaction is quenched with water and the mixture is extracted with ethyl acetate. The organic extract is washed with water and concentrated. The residue is purified by silica gel chromatography (0.5% methanol / dichloromethane) to give 322 mg of the title compound.

¹ H-NMR (CDCl 3 δ: 3.20 (d, 1H, J = 18), 3.47 (d, 1H, J = 18), 3.60 (d, 1H, J = 16), 3.66 (d, 1H, J = 16), 3.79 (s, 3H), 4.95 (m, 3H), 5.22 (d, 1H, J = 12), 5.25 (d, 1H, J = 12), 5.85 (dd, 1H, J = 5.8), 6.53 (d, 1H, J = 8), 6.84 (d, 2H, J = 9), 7.2-7 , 4 (m, 7H).

Example 3. Trifluoroacetic acid salt of (7R) -7 - [(phenylacetyl) amino] -3- (4-isothiouridomethyl-1,2,3-thiadiazol-5-ylthio) -3-cefem-4-carboxylic acid

A solution of (7R) -7 - [(phenylacetyl) amino] -3- (4-chloromethyl-) 4-methoxybenzylic ester solution

1,2,3-thiadiazol-5-ylthio) -3-cefem-4-carboxylic acid (70 mg, 0.12 mmol), thiourea (7.6 mg, 0.1 mmol) and sodium iodide (15 mg , 0.1 mmol) in anhydrous acetonitrile (3 ml) was stirred at room temperature overnight. The mixture is concentrated and triturated with dichloromethane to remove unreacted starting material. The residue was redissolved in acetone (2 ml) and filtered. The filtrate is concentrated to dryness to give 60 mg of (7R) -7 - [(phenylacetyl) amino] -3- (4-isothiouridomethyl-1,2,3-thiadiazole-5-ylthio) 4-methoxybenzyl acid ester. -3-cefem-4-carboxfic, iodide salt, in the form of a yellowish solid.

¹ H-NMR (acetone-d ₆ ) δ: 3.56 (d, 1H, J = 18), 3.66 (d, 1H, J = 16), 3.72 (d, 1H, J = 16) , 3.80 (s, 3H), 3.86 (d, 1H, J = 18), 5.06 (d, 1H, J = 15), 5.10 (d, 1H, J = 15), 5 , 28 (m, 3H), 5.88 (dd, 1H, J = 5.8), 6.91 (d, 2H, J = 9), 7.2-7.4 (m, 7), 8 , 32 (d, 1H, J = 8).

A mixture of (7R) -7 - [(phenylacetyl) amino] -3- (4-isothiouridomethyl-1,2,3-thiadiazol-5-ylthio) -3-cefem-4-carboxylic acid 4-methoxybenzylic ester, iodide salt (60 mg), anisole (0.1 ml) and trifluoroacetic acid (1 ml) were stirred at 0 ° C for 30 min and then concentrated to dryness. The residue is triturated sequentially with dichloromethane (40 ml) and water (0.5 ml) to give 38 mg of the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 3.41 (d, 1H, J = 18), 3.48 (d, 1H, J = 14), 3.55 (d, 1H, J = 14) , 3.69 (d, 1H, J = 18), 4.86 (d, 1H, J = 15), 4.94 (d, 1H, J = 15), 5.14 (d, 1H, J = 5), 5.72 (dd, 1H, J = 5.8),

7.1-7.3 (m, 7H), 9.18 (d, 1H, J = 8).

RO 119830 Β1

Example 4. (7R) -7-amino-3- (4-chloromethyl-1,2,3-thia-1-diazole-5-yl) -3-cefem-4-carboxylic acid 4-methoxybenzylic ester

To a solution of (7R) -7 - [(phenylacetyl) amino] -3- (4-chloro-3-methyl-1,2,3-thiadiazole-5-ylthio) -3-ketem- 4-methoxybenzylic ester solution. 4-carboxylic acid (604 mg, 1.68 mmol) and pyridine (0.271 ml, 3.36 mmol) in dichloromethane (20 ml) dropwise with a solution of phosphorus pentachloride 5 (208 mg, 2.68 mmol). in dichloromethane (10.7 ml) and stirred at -10 ° C for 2 h. After cooling to -40 ° C, isobutanol (1.55 ml) was added and the resulting mixture was stirred at -10 °. C for 4 h. 7 The reaction is quenched with water and the mixture is extracted with dichloromethane. The organic extract was washed with saturated aqueous sodium bicarbonate and concentrated. The residue was purified by chromatography 9 with silica gel (10% methanol / dichloromethane) to give 599 mg of the title compound.

H-NMR (CD ₃ OD) δ: 3.45 (d, 1H, J = 18), 3.65 (d, 1H, J = 18), 3.76 (s, 3H), 4.75 ( 1H, supra-11 with water), 4.98 (s, 2H), 5.05 (d, 1H, J = 5), 5.23 (s, 2H), 6.82 (d, 2H, J = 9), 7.26 (d, 2H, J = 9).

Example 5. 4-Chloro-3-hydroxymethylpyridine 13

To a solution of 4-chloro-3-pyridyl carboxydehyde (140 mg, 1.0 mmol) in THF (1 ml), methanol (1 ml) is added at 0 ° C, followed by the addition of sodium borohydride ( 75 mg, 15 2.0 mmol). After 1 h, acetic acid (0.15 ml) was added and the reaction mixture was evaporated to dryness in a rotary evaporator at room temperature. The solid residue was chromatographed on a 17 column silica gel (1% MeOH / dichloromethane) to give 60 mg (42%) of the title compound.

H-NMR (CDCl ₃ ) δ: 4.30 (wide s, 1H), 4.80 (s, 2H), 7.30 (d, 1H, J = 5), 8.34 (d, 1H, J = 5), 19 8.62 (s, 1H).

Example 6. (7R) -7 - [(phenylacetyl) amino] -3- (3-hydroxy-21-methylpyrid-4-ylthio) -3-cefem-4-carboxylic acid 4-methoxybenzyl ester

To a solution of 4-chloro-3-hydroxymethylpyridine (60 mg, 0.42 mmol) in DMF (1 ml) at room temperature, under nitrogen, potassium thioacetate (71 mg, 0.63 mmol) is added. . After stirring overnight, the solvent is removed in a rotary evaporator. The residue was washed with ethyl 25 ether and taken up in 10% MeOH / dichloromethane. The insoluble material is filtered and the filtrate is concentrated in a rotary evaporator. The residual material was dissolved in MeOH (3 ml) and 27 aqueous sodium hydroxide (0.5 ml, 3 M) was added. After overnight reaction at room temperature, the reaction mixture is acidified with hydrochloric acid M, evaporated to dryness in a rotary evaporator 29 and partitioned between a saturated solution of sodium bicarbonate and ethyl acetate. The organic layer is dried over sodium sulfate and the solvent is removed in a rotary evaporator. The residue was dissolved in MeOH and 4-methoxybenzyl ester (7R) -7 - [(phenylacetyl) amino] -3-trifluoromethanesulfonyloxy-3-cefem-4-carboxylic acid (240 mg, 0.42 mmol) was added. followed by the addition of 33 dichloromethane stations. After an overnight reaction at room temperature the reaction mixture is partitioned between a 5% solution of sodium bicarbonate and ethyl acetate. Purification on silica-gel (Chromatotron, 2% MeOH / dichloromethane) gave the title compound (60mg, 25%).

H-NMR (CDCl ₃ ) δ: 3.15 (d, 1H, J = 18), 3.55 (d, 1H, J = 18), 3.63 (d, 1H, J = 18), 3 , 68 (d, 37 1H, J = 18), 3.78 (s, 3H), 4.61 (d, 1H, J = 13), 4.66 (d, 1H, J = 13), 5, 05 (d, 1H, J = 5), 5.08 (d, 1H, J = 13), 5.25 (d, 1H, J = 13), 5.89 (dd, 1H, J = 9.5 ), 6.76 (d, 2H, J = 8), 7.05 (m, 2H), 7.16 (d, 21H, 39 J = 8), 7.32 (m, 5H), 8.40 (d, 1H, J = 5), 8.48 (s, 1H).

EXAMPLE 7 (7R) -7 - [(Phenylacetyl) amino] -3- (3-chloro-41-tyrid-4-ylthio) -3-cefem-4-carboxylic acid 4-methoxybenzylic ester

To a solution of (7R) -7 - [(phenylacetyl) amino] -3- (3-hydroxy-43-methylpyrid-4-ylthio) -3-cefem-4-carboxylic acid 4-methoxybenzylic ester (112 mg, 0.194 mmol) and lithium chloride (14 mg,

Diisopropylethylamine (0.101 mL, 0.581 mmol) and methanesulfonyl chloride (0.045 mL, 0.581 mmol) were added to DMF at 0 ° C. After 45 minutes, the reaction mixture is partitioned between water and ethyl acetate / hexane (v / v, 3/1). Purification on silica gel (Chromatotron, 2% MeOH / 47 dichloromethane) afforded the title compound (52 mg, 45%).

Β1 EN 119 830 ^1H-NMR _(CDCl3) δ: 3.17 (d, 1H, J = 18), 3.59 (d, 1H, J = 18), 3.63 (d, 1H, J = 18 ), 3.68 (d,

1H, J = 18), 3.77 (s, 3H), 4.54 (d, 1H, J = 13), 4.66 (d, 1H, J = 13), 5.06 (d, 1H, J = 5), 5.08 (d, 1H,

J = 13), 5.22 (d, 1H, J = 13), 5.90 (dd, 1H, J = 9.5), 6.76 (d, 2H, J = 8), 6.95 ( d, 1H, J = 9), 7.07 (d, 1H,

J = 5), 7.15 (d, 2H, J = 8), 7.30 (m, 5H), 8.41 (d, 1H, J = 5), 8.45 (s, 1H).

Example 8. (7R) -7 - [(phenylacetyl) amino] -3- (3-isothiouridomethylpyrid-4-ylthio) -3-cefem-4-carboxylic acid 4-methoxybenzyl ester, hydrochloride salt

To a solution of 4-methoxybenzyl ester of (7R) -7 - [(phenylacetyl) amino] -3- (3-chloromethylpyrid-4-ylthio) -3-cefem-4-carboxylic acid, (52 mg, 0.087 mmol) In ethanol (0.4 ml) and dichloromethane (0.1 ml), thiourea (7 mg, 0.095 mmol) was added at room temperature. After the reaction overnight, the solvents are removed in a rotary evaporator and the residue is triturated with ethyl ether. The solid precipitate was then dried in vacuo to give the title compound (56 mg, 96%).

¹ H-NMR (CDCl ₃ / CD ₃ OD) δ: 3.14 (d, 1H, J = 10), 3.53 (d, 1H, J = 10), 3.58 (s, 2H), 3 , 73 (s, 3H), 4.40 (s, 2H), 5.03 (d, 1H, J = 5), 5.12 (d, 1H, J = 9), 5.15 (d, 1H) , J = 9), 5.75 (d, 1H, J = 5), 6.74 (d, 2H, J = 10), 7.10 (d, 1H, J = 5), 7.14 (d , 2H, J = 10), 7.25 (m, 5H), 8.30 (d, 1H, J = 5), 8.45 (s, 1H).

Example 9. Trifluoroacetic acid (7R) -7 - [(phenylacetyl) amino] -3- (3-isothiouridomethylpyrid-4-ylthio) -3-cefem-4-carboxylic acid salt

To a solution of (7R) -7 - [(phenylacetyl) amino acids 4-methoxybenzyl ester hydrochloride.

3- (3-Isothiouridomethylpyrid-4-ylthio) -3-cefem-4-carboxylic acid (56 mg, 0.083 mmol) in dichloromethane (1 ml), anisole (0.1 ml) was added followed by the addition of trifluoroacetic acid ( 1 ml). After 30 minutes, the reaction mixture is concentrated in a rotary evaporator and the residue is triturated with ethyl ether. The precipitate was washed repeatedly by decanting with fresh portions of ethyl ether and dried in vacuo to give the title compound (49 mg, 79).

¹ H-NMR (CD ₃ OD) δ: 3.20 (d, 1H, J = 18), 3.58 (d, 1H, J = 13), 3.62 (d, 1H, J = 13), 3.83 (d, 1H, J = 18), 4.56 (d, 1H, J = 10), 4.60 (d, 1H, J = 10), 5.25 (d, 1H, J = 5) ), 5.78 (d, 1H, J = 5), 7.28 (m, 5H), 7.43 (d, 1H, J = 5), 8.45 (d, 1H, J = 5), 8.55 (s, 1H).

Example 10. (7R) -7 - [(Z) -2- (N-triphenylmethyl-aminothiazole-) 4-methoxybenzylic ester.

4- yl) -2- (triphenylmethoxyimino) -acetamido] -3 (4-chloromethyl-1,2,3-thiadiazol-5-ylthio) -3-cefem-4-carboxylic acid

To a suspension of (Z) -2- (N-triphenylmethylaminothiazol-4-yl) -2- (triphenylmethoxy-imino) sodium acetate (2.11 g, 3.05 mmol) in DMF (4 ml), chloride is added of methanesulfonyl (0.28 ml) at -60 ° C and stirred at this temperature for 1.5 h. The solution is then added to a solution of 4-methoxybenzylic acid hydrochloride (7R) -7-. amino-3- (4-chloromethyl-1,2,3-thiadiazol-5-yl) thio-3-hexaf-4-carboxylic acid (920 mg, 1.88 mmol) and diisopropylethylamine (0.4 ml) in DMF (2 ml) at -10 ° C and stirred for 1 h. The reaction mixture is poured over ice-water, and the resulting precipitate is collected by filtration. The filter cake is purified by silica gel column chromatography (0.5% methanol / dichloromethane) to give 558 mg of the title compound.

Ή-NMR (CDCl ₃ ) δ: 3.07 (d, 1H, J = 18), 3.44 (d, 1H, J = 18), 3.81 (2H), 4.96 (2H), 5 , 06 (1H), 6.07 (1H), 6.43 (s, 1H), 6.80 (wide s, 1H), 6.88 (1H), 7.25-7.45 (40H) .

Example 11. (7R) -7 - [(Z) -2- (aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- (4-isothio-ureido-methyl-1,2) trifluoroacetate salt 3-thiadiazol-5-ylthio) -3-cephem-4-carboxylic acid

A solution of (7R) -7 - [(Z) -2- (N-triphenylmethylaminothiazol-4-yl) -2- (triphenylmethoxyimino) acetamido] -3- (4-chloromethyl-1,2,3) 4-methoxybenzylic ester solution -thiadiazol-5-ylthio) -3-cefem-4-carboxylic acid (221 mg, 0.19 mmol), sodium iodide (34 mg, 0.23 mmol) and thiourea (14 mg, 0.18 mmol) in acetonitrile (10 ml) was stirred at 45 ° C for 3 h. The resulting mixture was partitioned between water and ethyl acetate. The ethyl acetate layer is washed with water and concentrated. The residue is triturated to obtain the isothiouronium salt, which is subjected, for the most part, to the same conditions for protection, as those used in Example 9, to obtain 27 mg of the title compound.

Ή-NMR (D ₂ O) δ: 3.48 (d, 1H, J = 18), 3.84 (d, 1H, J = 18), 5.39 (s, 1H), 5.90 (s , 1H), 7.16 (s, 1H) .--——

RO 119830 Β1

Example 12. 4-Ethoxycarbonyl-5- [2- (phenylsulfonyl) ethylthio] thiazole 1

To a solution of potassium tert-butoxide (496 mg, 4.4 mmol) in 10 ml of THF add a solution of ethyl isocyanacetate (0.48 ml, 4.4 mmol) in 5 ml of THF at -40 'C and the reaction mixture is stirred. then for 10 min. After cooling the reaction mixture to -60 ° C, a solution of carbon disulfide in 5 ml of THF is added. The resulting mixture was allowed to warm to O'C and 2-iodoethyl-phenyl-sulfone (4.4 mmol) was added. The mixture is then stirred under reflux conditions for 5 hours. After cooling to room temperature, water and 7 ethyl acetate are added. The aqueous layer is brought under acidic conditions with dilute hydrochloric acid and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The crude residue was purified by chromatography to give the title compound (890 mg, 56%). 11 'H-NMR (CDCl ₃ ) δ: 1.40 (t, 3H, J = 7), 3.3-3.5 (m, 4H), 4.40 (q, 2H, J = 7), 7.6 (t, 2H, J = 8), 7.70 (t, 1H, J = 8), 7.93 (d, 2H, J = 8) and 8.64 (s, 1H). 13

Example 13. 4-H / drox / meW-5-f2-ffen // su / fon / 7) and / 7t / ojtiazo /

To a solution of 4-ethoxycarbonyl-5- [2- (phenylsulfonyl) ethylthio] thiazole (702 mg, 2 mmol) in 20 ml 15 of THF, lithium borohydride (2M, 1 ml) and methanol (0.16) are added. ml, 4 mmol) at -30 * C. The reaction mixture was allowed to warm slowly to room temperature and stirred for 17 nights. The solvent is removed under reduced pressure and the crude residue is subjected to chromatography, using dichloromethane and methanol, as eluent, to give the title compound 19 (400 mg, 65%).

H-NMR (CDCl ₃ ) δ: 2.55 (s, 1H), 3.00 (t, 2H, J = 6), 3.40 (t, 2H, J = 6), 4.71 (s , 2H), 7.6 (t, 21 2H, J = 7), 7.68 (t, 1H, J = 7), 7.82 (d, 2H, J = 7) and 8.80 (s, 1H).

Example 14. (7R) -7 - [(Z) -2- (N-triphenylmethyl-aminothia-23 zol-4-yl) -2- (triphenHmethoxyimino) -acetamido] -3- (4-methoxybenzylic acid 4-methoxy ester) -hidroximetiltiazol-5-ylthio) -3-cephem-4-carboxylic acid

To a solution of 4-hydroxymethyl-5- [2- (phenylsulfonyl) ethylthio] thiazole (39 mg) in 1 ml of DMF, potassium tert-butoxide (14 mg) is added, and the resulting mixture is stirred in then for 2 hours. After cooling the reaction solution to -40 ° C, a solution of (7R) -7 - [(Z) -2- (N-triphenylmethylaminothiazole) 4-methoxy-27-benzyl ester is added. -4-yl) -2- (triphenylmethoxyimino) acetamido] -3-trifluoromethane-sulfonyloxy-3-cefem-4-carboxylic acid (104 mg) in 1.5 ml of DMF. The mixture is allowed to warm slowly to 0 ° C, quench with aqueous, dilute solution of ammonium chloride and extract with ethyl acetate and hexane. The solvent was removed under reduced pressure and the crude residue was purified by chromatography to give the title compound (61 mg).

H-NMR (CDCl ₃ ) δ: 3.28 (q, 2H, J = 8), 3.82 (s, 3H), 4.72 (q, 2H, J = 8 Hz), 4.98 ( d, 1H, 33 J = 4), 5.25 (q, 2H, J = 8), 5.96 (q, 1H, J = 4), 6.42 (s, 1H), 6.85 (s , 1H), 6.93 (d, 2H, J = 7), 7.20-7.42 (m, 33H) and 8.8 (s, 1H). 35

Example 15. (7R) -7 - [(Z) -2- (N-triphenyl-methyl-aminothiazol-4-yl) -2- (triphenylmethoxyimino) -acetamido] -3- (4-) 4-methoxybenzylic acid ester. chloromethylthiazole-5-ylthio) -3-cefem-4-carboxylic acid 37

Thionyl chloride (0.016 ml) is added to O'C over DMF (1 ml) and the resulting mixture is further stirred at this temperature for 30 min. The resulting solution is introduced by a cannula over a solution of (7R) -7 - [(Z) -2- (Ntriphenylmethylaminothiazol-4-yl) -2- (triphenyl-methoxyimino) -acetamido acid over a 4-methoxybenzylic ester solution. ] -3- (4-hydroxymethythiazol-5-ylthio) -3- 41 cefem-4-carboxylic acid (61 mg) in 1 ml of DMF and further stirred at this temperature for one hour. The reaction solution was diluted with ethyl acetate and hexane and washed with water. The wind is removed under reduced pressure and the crude residue is purified by chromatography to give the title compound (43 mg). 45 'H-NMR (CDCl ₃ ) δ: 3.22 (q, 2H, J = 12), 3.80 (s, 3H), 4.78 (q, 2H, J = 8), 5.04 ( d, 1H, J = 4),

5.30 (q, 2H, J = 5), 6.00 (q, 1H, J = 4), 6.42 (s, 1H), 6.72 (s, 1H), 6.92 (d, 2H, J = 7), 7.08 (d, 1H, 47

J = 4), 7.20-7.45 (m, 32H) and 8.95 (s, 1H). --.-- 31

RO 119830 Β1

Example 16. (7R) -7 - [(Z) -2- (N-triphenylmethyl-aminothiazol-4-yl) -2- (triphenylmethoxyimino) -acet-amido] -3- (4-) 4-methoxybenzyl acid ester. isothioureidomethyl-tiazol'5-ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (N-triphenHmethyl-aminothiazol-4-yl) -2- (triphenylmethoxyimino) acetamido) -3- (4-chloromethylthiazol-5-yl) 4-methoxybenzylic ester. thio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (N-triphenylmethyl-aminothiazole-4-yl) -2- (triphenylmethoxyimino) -acetamido] -3- (4-chloromethylthiazole-5-ylthio) 4-methoxybenzylic acid is dissolved. ) -3-cefem-4-carboxylic (43 mg) in 2 ml of acetonitrile, to which are added thiourea (4.5 mg) and sodium iodide (13 mg). The resulting mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure, and the crude residue is purified by flash chromatography to give the title compound (40 mg).

¹ H-NMR (CDCIg / CDgOD) δ: 3.2 (q, 2H, J = 12), 3.80 (s, 3H), 4.4 (q, 2H, J = 12), 5.02 ( d, 1H, J = 4), 5.25 (q, 2H, J = 5), 5.85 (d, 1H, J = 4), 6.45 (s, 1H), 6.90 (d, 2H, J = 7), 7.2-7.4 (m, 32H) and 9.00 (s, 1H).

Example 17. (7R) -7 - [(Z) -2- (aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- (4-isothiouridornetylthiazole-5-yl) -3- trifluoroacetate salt. cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (N-triphenylmethylamino-thiazol-4-yl) -2- (triphenylmethoxyimino) -acetamido] -3- (4-isothiouridomethylthiazole-5- (4-methoxy-benzyllic acid) ester. Iltio) -3-cefem-4-carboxylic acid (40 mg) is dissolved in 0.1 ml of anisole and 0.9 ml of dichloroacetic acid. The resulting mixture was stirred at room temperature for 3 h and then precipitated by addition of diethyl ether (100 ml). The precipitate was filtered and subjected to HP-20 reverse phase chromatography to give the title compound.

H-NMR (D ₂ O) δ: 3.60 (q, 2H, J = 6), 4.60 (q, 2H, J = 10), 5.20 (d, 1H, J = 4), 5.80 (d, 1H, J = 4), 6.90 (s, 1H) and 9.13 (s, 1H).

IR (KBr): 997.1042, 1180, 1349.1386.1533.1615.1655 and 1768 cm ^-1 .

Exemplul18. (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (triphenylmethoxyimino) acetic acid

To a solution of (Z) -2- (2-aminothiazol-4-yl) -2- (triphenylmethoxyimino) acetic acid (5.81 g, 13.47 mmol) in DMF (30 ml), at room temperature (1 ml), N-chlorosuccinimide (1.80 g, 13.47 mmol) is added. After the reaction, overnight, the reaction mixture is poured over water (about 500 ml), and the resulting precipitate is filtered, washed with water and then with ethyl acetate and dried in vacuo to give 4.43 g ( 71%) of the title compound.

¹³ C-NMR (CDCl ₃ ) δ: 108,5,125,6,126,2,126,6,12,3,134.7 141.8,146,5,162.1,163.3.

Example 19. (7R) -7 - [(Z) -2- (2-amino-5-chlothiazol-4-yl) -2 (triphenylmethoxyimino) -acetamido] -3-chloro-3-cefem-acid diphenylmethyl ester. 4-carboxylic acid

To a solution of toluenesulfonic acid salt of diphenylmethyl ester of 7-amino-3-chlorocephalosporanic acid (5.0 g, 8.72 mmol) in anhydrous THF (1 OOml), pyridine (0.63 g, 10.0) is added mmol) at room temperature, followed by addition of (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (triphenylmethoxy-imino) acetic acid (5.81 g, 13.47 mmol). The resulting paste is cooled to -15 ° C and a further portion of pyridine (1.42 g, 22.5 mmol) is added, followed by the dropwise addition of phosphorus oxychloride (1.64 g, 17, 5 mmol), keeping the reaction temperature below -10 ° C. After 30 min. The reaction mixture was added ethyl acetate (200 ml), followed by the addition of water (150 ml). The aqueous layer is completely extracted with ethyl acetate and the combined organic extracts are dried over sodium sulfate and concentrated in vacuo to give the crude product, which is purified by flash column chromatography with silica gel (ethyl acetate / hexane, 3 / 1) to obtain the title compound (5.37 g, 65%).

Ή-NMR (CDCIg / CDgOD) δ: 3.35 (d, 1H, J = 18), 3.68 (d, 1H, J = 18), 5.07 (d, 1H, J = 5),

5.80 (wide s, 2H), 6.04 (dd, 1H, J = 9.5), 7.03 (s, 1H), 7.06 (d, 1H, J = 9), 7.22 -7.50 (m, 25H).

RO 119830 Β1

Example 20. (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- 1 (triphenylmethoxyimino) -acetamido] -3-mercapto-3- acid diphenylmethyl ester. cephem-4-carboxylic acid

To a solution of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- 3 (triphenylmethoxyimino) acetamido] -3-chloro-3- acid diphenylmethyl ester solution. cefem-4-carboxylic acid (4.0 g, 4.72 mmol) in DMF (30 ml), cooled to -20 ° C, sodium bisulfide powder hydrate (1.1 g) is added in a single portion , 5 19.6 mmol). After 15 min, the reaction mixture was poured onto 0.5 M monosodium phosphate (about 100 ml), extracted with ethyl acetate and the organic layer was washed very well with water. After 7 concentration in vacuo, the crude product was obtained as a yellow foam 3.8 g (95%). 9 'H-NMR (CDCl3 / CD ₃ OD) δ: 3.38 (d, 1H, J = 15), 4.43 (d, 1H, J = 15), 5.03 (d, 1H, J = 5), 5.80 (d, 1H, J = 5), 5.99 (wide s, 1H), 6.80 (s, 1H), 7.05-7.50 (m, 25H). 11

Example 21. 3-Chloromethyl-4-chloropyridine hydrochloride

Thionyl chloride (0.714 mL, 9.78 mmol) over anhydrous DMF (7 mL) was added at room temperature. After 30 min, the above solution is introduced through a cannula over 3 hydroxymethyl-4-chloropyridine solution (700 mg, 4.89 mmol) in DMF (3 ml). After 45 min, the product precipitated 15 by addition of anhydrous ether (100 mL), washed with ether and dried in vacuo to give 813 mg (84%) of the title compound. 17 'H-NMR (CD ₃ OD) δ: 5.00 (s, 2H), 8.31 (d, 1H, J = 5), 8.99 (d, 1H, J = 5), 9.18 (s, 1H).

Example 22. 3- (N-tert-butoxycarbonylaminoethylthiomethyl) -4-chloropyridine 19

To a solution of 3-chloromethyl-4-chloropyridine hydrochloride (513 mg, 2.59 mmol) in DMF (6 ml), sodium iodide (386 mg, 2.59 mmol), diisopropylethyl-21, was added to room temperature. amine (1.12 ml, 6.47 mmol) and 2- (N-tert-butoxycarbonylamino) -etantiol (458 mg, 2.59 mmol). After 2 h, the reaction mixture was partitioned between dilute HCl and ethyl acetate. Organic layer 23 was washed with water, dried over sodium sulfate and concentrated to afford 750 mg of oily product (96%), which was used in the next step without further purification. 25 'H-NMR (CDCl ₃ ) δ: 1.43 (s, 9H), 2.61 (m, 2H), 3.35 (m, 2H), 3.81 (s, 2H), 4.90 (s wide,

1H), 7.35 (d, 1H, J = 4), 8.40 (d, 1H, J = 4), 8.57 (s, 1H). 27

Example 23. (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol'4-yl) -2 (triphenylmethoxyimino) -acetamido] -3- (3-N) diphenylmethyl acid ester. - tert-butoxycarbonylamino-ethylthio-metHpin'd-4-Htio) -3-cefem- 29 4-carboxylic

To a solution of diphenylmethyl ester of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- 31 (triphenylmethoxyimino) acetamido] -3-mercapto-3- cefem-4-carboxylic acid (650 mg, 0.777 mmol) in DMF (3 ml) was added 3- (N-tert-butoxycarbonylaminoethylthiomethyl) -4-chloropyridine (242 mg, 0.80 mmol) 33 at room temperature. After the reaction overnight, the reaction mixture is partitioned between water and ethyl acetate. The organic layer is washed very well with water, dried over sodium sulfate and concentrated to obtain the crude product which is purified by radial silica gel chromatography (dichloromethane / methanol; v / v, 50/1) to give 220 mg of the title compound (26%). 37

Ή-NMR (CDCIg / CDgOD) δ: 1.23 (s, 9H), 2.32 (t, 2H, J = 6), 2.98 (d, 1H, J = 18), 3.06 (m , 2H), 3.40 (d, 1H, J = 18), 3.46 (s, 2H), 5.03 (d, 1H, J = 5), 5.52 (wide s, 1H), 5 , 94 (d, 1H, J = 5), 6.80 39 (s, 1H), 6.90 (d, 1H, J = 6), 7.00-7.22 (m, 25H), 8, 01 (d, 1H, J = 6), 8.08 (s, 1H).

Example 24. The salt with methanesulfonic acid (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- 41 (hydroxyimino) acetamido] -3- (3-aminoethylthiomethylpyrid) 4-ylthio) -3-cephem-4-carboxylic acid

To a solution of diphenylmethyl ester of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- 43 (triphenylmethoxyimino) -acetamido] -3- (3- N-tert -butoxycarbonylamino-ethylthiomethylpyrid-4-ylthio) -3-cefem4-carboxylic acid (1.0 g, 0.907 mmol) in dichloromethane (10 ml) and anisole (1.0 ml), added to 0'C 45 trifluoroacetic acid (13 ml). After 1.5 h, the reaction mixture was concentrated in vacuo, at room temperature and the oily residue was dissolved in 98% formic acid (20 ml). After 4 hours, at room temperature 47

EN 119830 rei1 king, formic acid is removed in vacuo and the residue dissolved in water (25 ml). The insoluble material is removed by centrifugation and the supernatant is purified on HP20 column by elution with water followed by 0.1 M ammonium acetate, water and finally eluting the product with acetonitrile / water (1/4). The eluate is concentrated to about 1/10 of the initial volume, and the resulting precipitate is filtered, washed with water and dried in vacuo to give the zwitterionic product (260 mg). The methanesulfonate salt is prepared by suspending the above material in water (15 mL), followed by the addition of methanesulfonic acid (1.0 M in water, 0.98 equiv.) And acetonitrile (5 mL). After dry evaporation of the resulting solution, the residue is dissolved in water (30 ml), centrifuged to remove the insoluble material, and the supernatant is lyophilized to obtain the title compound (274 mg, 44%).

H-NMR (D ₂ O) 5: 3.11 (s, 3H), 3.19 (m, 2H), 3.52 (m, 2H), 3.67 (d, 1H, J = 17) , 4.22 (d, 1H, J = 17), 4.33 (s, 2H), 5.76 (d, 1H, J = 4), 6.29 (d, 1H, J = 4), 7 , 93 (d, 1H, J = 4), 8.78 (d, 1H, J = 4), 8.87 (s, 1H).

Example 25. 3- (N-tert-Butoxycarbonylaminoethylthio) -4-chloropyridine

To a suspension of 4-chloropyridine hydrochloride (2 g) in 40 ml of anhydrous THF, freshly prepared LDA (2.5 eq) is added at -70 ° C, and the resulting mixture is further stirred at this temperature. , for 4 h. A solution of N, N'-di (fert-butoxycarbonyl) cystamine (2.5 g, 0.5 equiv) in 10 ml of THF was introduced through a cannula over the above solution. The reaction mixture was allowed to warm to 0 ° C, quench with water and then extracted with ethyl acetate. The solvent was removed under reduced pressure and the crude residue was purified by flash chromatography to give the title compound (0.95 g, 50%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.42 (s, 9H), 3.15 (t, 2H, J = 7), 3.38 (t, 2H, J = 7), 4.95 (s , 1H), 7.32 (d, 1H, J = 6), 8.35 (d, 1H, J = 6) and 8.60 (s, 1H).

Example 26. (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2 (triphenylmethoxyimino) -acetamido] -3- [3- (N-) diphenylmethyl acid ester. butoxicarbonilarnino tert-ethylthio) pyridyl-4-thio] -3-cephem-4-carboxylic acid

To a stirred solution of diphenylmethyl ester of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol4-yl) -2- (triphenylmethoxyimino) acetamido] -3-mercapto-3-cefem- 4-carboxylic acid (6.7 g, 7.8 mmol) in 20 ml of anhydrous DMF, 3- (N-tert-butoxycarbonylaminoethylthio) -4-chloropyridine (2.3 g, 7.8 mmol) is added to - 20 ° C. The reaction mixture is allowed to warm slowly to room temperature and stir overnight. The reaction mixture was diluted with ethyl acetate and hexane and washed with water. The solvent was removed under reduced pressure, and the crude residue was purified by chromatography to give the title compound (6 g, 68%) as a yellow solid.

¹ H-NMR (CDCl ₃ ) δ: 1.40 (s, 9H), 2.75 (t, 2H, J = 7), 3.10 (t, 2H, J = 7), 3.15 (d , 1H, J = 14), 3.60 (d, 1H, J = 14), 4.95 (s, 1H), 5.20 (d, 1H, J = 4), 5.90 (s, 2H) ), 6.25 (q, 1H, J = 4), 6.85 (d, 1H, J = 4), 6.90 (s, 1H), 7.15-7.4 (m, 26H), 8.1 (s, 1H), 8.21 (d, 1H, J = 7).

Example 27. (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2 (hydroxyimino) acetamido] -3- (3-aminoethylthiopyrid-4-ylthio) trifluoroacetate salt ) -3-cephem-4-carboxylic acid

To a solution of diphenylmethyl ester of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2 (triphenylmethoxyimino) -acetamido] -3- [3- (N -tert-butoxycarbonyl-aminoethylthio) -pyridyl-4-thio] -3-cefem4-carboxylic acid (6 g) in 10 ml of dichloromethane and 1 ml of anisole add 10 ml of trifluoroacetic acid at 0 ° C and the resulting solution shake at room temperature for one hour. After the solvent was removed, the residue was redissolved in 20 ml of formic acid and stirred at room temperature overnight. The solvent is removed under reduced pressure. The residue was dried under high vacuum and then triturated with ethyl acetate. The resulting solid is subjected to reverse phase chromatography on an Amberchrom column (0.1% aqueous trifluoroacetic acid / acetonitrile) to give the title compound (1.5 g, 48%).

RO 119830 Β1 'H-NMR (D ₂ O) δ: 3.5-3.7 (m, 4H), 3.8 (d, 1H, J = 14), 4.4 (d, 1H, J = 14), 5.84 (d, 1H, J = 4), 1

6.4 (d, 1H, J = 4), 7.65 (d, 1H, J = 6f, 8.82 (d, 1H, J = 6) and 9.02 (s, 1H). IR (KBr ): 778, 1042, 1173,

1541, 1610, 1780, 3187 cm ' ¹ . 3

Example 128. (7R) -7 - [(Z) -2- (aminothiazol-4-yl) -2- (triphenylmethoxyoxyimino) acetamido] -3- (4- (2-tert-butoxycarbonylaminoethyl-thiomethyl) benzhydryl ester. ) -1,2,3-thiadiazol-5-ylthio) -3-5 cefem-4-carboxylic acid

To a solution of 4 - [(2-tert-butoxycarbonylaminoethyl) thiomethyl] -5- (2-ethoxy-carbonylethyl) thio-1,2,3-7

1,2,3-thiadiazole (181 mg, 0.44 mmol) in ethanol (5 ml) was added sodium methoxide in methanol (0.55 M, 1 ml) and concentrated. The residue is triturated with hexane-ethyl acetate (9: 1), mixed with 9 (7R) -7 - [[(Z) -2- (2-aminothiazol-4-yl) -2 diphenylmethyl acid ester. - (triphenylmethoxyimino) acetyl] amino] -3-chloro-3-cefem-4-carboxylic acid (200 mg, 0.25 mmol) and dissolved in a mixture of 11 solvents of ethanol and dichloromethane. The solution was stirred at room temperature for 16 h and concentrated. The crude product was purified by silica gel column chromatography (13% methanol / dichloromethane) to give 100 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H), 2.68 (2H), 3.19 (d, 1H, J = 18), 3.33 (2H + 1H), 4.03 ( 2H), 15 4.88 (wide s, 1H), 5.09 (1H), 5.93 (wide s, 2H), 6.44 (s, 1H), 7.03 (1H), 7.20 -7.45 (25H).

Example 29. Dichloroacetic acid salt of (7R) -7 - [(Z) -2- (aminothiazol-4-yl) -2- (hi-17 droxyimino) acetamido] -3- (4- (2-aminoethylthiomethyl) ) -1,2,3-thiadiazol-5-ylthio) -3-cephem-4-carboxylic acid

Dissolve (7R) -7 - [(Z) -2- (aminothiazol-4-yl) -2- (triphenylmetho-19xioxyimino) acetamido] -3- (4- (2-aminoethylthiomethyl) -1) diphenylmethyl ester. , 2,3-thiadiazol-5-ylthio) -3-cefem-4-carboxylic acid (82 mg, 0.076 mmol) in 0.8 ml of dichloroacetic acid containing 5% anisole and stirred at room temperature overnight. Excess diethyl ether is added, and the resulting precipitate is collected by filtration. The filtration cake is purified by reverse-phase column chromatography 23 HP-20 to obtain 16 mg of the title compound.

H-NMR (DMSO-d ₆ ) δ: 2.64 (2H), 2.90 (2H), 3.4 (1H, superimposed on water), 3.82 (d, 1H, 25 J = 17) , 4.04 (d, 1H, J = 15), 4.14 (d, 1H, J = 15), 5.17 (d, 1H, J = 5), 5.74 (dd, 1H, J = 5.8), 6.64 (S, 1H), 7.08 (s, 1H), 9.50 (d, 1H, J = 8). 27

Example 30. 3- (2-N-tert-Butoxycarbonylaminoethoxymethyl) -4-chloropyridine

A diphthalic mixture of 4-chloro-3-chloromethylpyridine hydrochloride (396 mg, 2 mmol), N-29 tert-butoxycarbonylaminoethanol (132 mg, 2 mmol) and benzyltriethylammonium bromide (544 mg, 2 mmol) in toluene (20 ml ) and 50% aqueous sodium hydroxide solution is stirred vigorously at room temperature for 24 hours. The organic layer is taken up and concentrated to obtain 490 mg of the title compound. 33 ¹ H-NMR (CDCl 3) δ: 1.46 (s, 9H), 3.39 (2H), 3.65 (2H), 4.64 (s, 2H), 4.90 (wide s, 1H) )

7.33 (d, 1H, J = 5), 8.46 (d, 1H, J = 5), 8.64 (s, 1H). 35

Example 31. (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2 (triphenylmethoxyimino) -acetamido] -3- (3- (2- tert-butoxycarbonylaminoeioxy-methyl) pyrid-4-ylthio) -3-cefem-37 4-carboxylic under conditions almost identical to those used in Example 26, diphenylmethyl ester of (39R) -7 - [(Z) - 2- (2-amino-5-chlorothiazol-4-yl) -2- (triphenylmethoxy-imino) acetamido] -3-mercapto-3-cefem-4-carboxylic acid reacts with 3- (2-N-tert-butoxycarbonylaminoethoxymethyl) -4-chloropyridine to obtain the title compound.

H-NMR (CDCl3) δ: 1.42 (9H), 3.11 (d, 1H, J = 18), 3.24 (2H), 3.40 (2H), 3.46 (d, 1H) , 43 J = 18), 4.30 (2H), 4.83 (wide s, 1H), 5.17 (1H), 5.72 (wide s, 2H), 6.20 (1H), 6, 99 (s, 1H), 7.25-7.45 (25H), 8.28 (1H), 8.33 (4HȚ—— ........ 45

RO 119830 Β1

Example 32. Trifluoroacetate salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2 (hydroxyimino) acetamido] -3- (3- (2-aminoethoxymethylenepyrid) salt -4-ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (triphenylmethoxyimino) -acetamido] -3- (3- (2-tert-) acid diphenylmethyl ester). butoxycarbonylaminoethoxymethyl) -pyrid-4-ylthio) -3-cefem-4-carboxylic acid is said to be deprotected under conditions almost identical to those used in Example 27, to obtain the title compound.

Ή-NMR (D ₂ O) δ: 3.35 (2H), 3.45 (d, 1H, J = 18), 3.91 (2H), 4.00 (d, 1H, J = 18), 5.52 (d, 1H, J = 5), 6.04 (d, 1H, J = 5), 7.73 (d, 1H, J = 6), 8.57 (d, 1H, J = 6) ), 8.65 (s, 1H).

Example 33. 3- (N-tert-Butoxycarbonylaminoethylsulfonylmethyl) -4-chloropyridine

To a solution of 3- (N-fef | -butoxycarbonylaminoethyl) thiomethyl) -4-chloropyridine (302 mg, 1 mmol) in a mixture of ethyl acetate (10 ml) and methanol (5 ml) was added acid methanesulfonic acid (144 mg, 1.5 mmol). 3-Chloroperoxybenzoic acid (700 mg) was added and stirred at room temperature for 5 h. The reaction was quenched with saturated aqueous sodium thiosulphate solution. The solution is neutralized with 10% sodium hydroxide and extracted with ethyl acetate. The ethyl acetate extract was dried over sodium sulfate and concentrated to dryness to give 286 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H), 3.22 (2H), 3.66 (2H), 4.50 (s, 2H), 5.21 (wide s, 1H) , 7.42 (d, 1H, J = 5), 8.54 (s, 1H, J = 5), 8.72 (1H).

Example 34. (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2 (triphenylmethoxyimino) -acetamido] -3- (3-N-tert) diphenylmethyl ester -butoxycarbonylaminoethyl-sulfonylmethylpyrid-4-ylthio) -3-cefem-4-carboxylic acid under conditions almost identical to those used in Example 26, (7R) -7 - [(Z) -2- (2-amino-) diphenylmethyl ester. 5-Chlorothiazol-4-yl) -2- (triphenylmethoxy-imino) acetamido] -3-mercapto-3-cefem-4-carboxylic acid reacts with 3- (N-tert-butoxycarbonylaminoethylsulfonylmethyl) -4-chloropyridine, to get the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H), 3.20 (3H), 3.66 (3H), 4.48 (s, 2H), 5.19 (1H), 7.25 -7.45 (25H), 8.50 (s, 1H, J = 5), 8.70 (1H).

Example 35. (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2 (hydroxyimino) acetamido] -3- (3-aminoethylsulfonylmethylpyrid-4-) trifluoroacetate salt. ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (triphenylmethoxyimino) -acetamido] -3- (3-N-tert-butoxycarbonylaminoethylsulfonylmethyl acid diphenylmethyl ester) -pyrid-4-ylthio) -3-cefem-4-carboxylic acid is said to be deprotected, under conditions almost identical to those used in Example 27, to obtain the title compound.

¹ H-NMR (D ₂ O) δ: 3.47 (d, 1H, J = 18), 3.70 (2H), 3.85 (2H), 4.02 (d, 1H, J = 18) , 5.07 (s, 2H), 5.52 (d, 1H, J = 5), 6.03 (d, 1H, J = 5), 7.79 (d, 1H, J = 6), 8 , 64 (d, 1H, J = 6), 8.76 (s, 1H).

Example 36. 3- (4-N-tert-Butoxycarbonylaminobutin-1-yl) -4-chloropyridine

4-Chloro-3-chloromethylpyridine hydrochloride reacts with 3-f-BOC-amino-1-propine under phase transfer conditions, described in Example 30, to obtain the title compound.

¹ H-NMR (CDCl 3) δ: 1.4-1.6 (9H, rotomeric mixture), 4.0-4.2 (2H), 7.32 (d, 1H, J = 5), 8.43 (d, 1H, J = 5), 8.53 (s, 1H).

Example 37. (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2 (triphenylmethoxyimino) -acetamido] -3- (3- (4-) diphenylmethyl acid ester. N-tert-butoxycarbonylamino-butin-1-yl) pyrid4-ylthio) -3-cefem-4-carboxylic under conditions almost identical to those used in Example 26, (7R) -7 - [(Z) -2- diphenylmethyl ester. (2-amino-5-chlorothiazol-4-yl) -2- (triphenylmethoxy-imino) acetamido] -3-mercapto-3-cephe-4-carboxylic acid reacts with 3- (4-N-tert-butoxycarbonylaminobutin-1-yl) -4-chloropyridine to obtain the title compound.

RO 119830 Β1 'H-NMR (CDCl ₃ ) δ: 1.4-1.8 (9H), 3.10 (d, 1H, J = 18), 3.47 (d, 1H, 3 = 18), 3.85 (2H), 5.16 1 (1H), 5.62 (wide s, 2H), 6.13 (1H), 7.00 (1H), 7.2 -7.5 (25H), 8.35 (2H).

Example 38. (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- 3 (hydroxyimino) acetamido] -3- (3- (4-) trifluoroacetate acid salt amino-2-butyn-1-yl) pyrid-4-ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (triphenylmethoxy-5-imino) acetamido] -3- (3- (4-) acid diphenylmethyl ester. N-tert-butoxycarbonylaminobutin-1-yl) pyrid-4-ylthio) -3-cefem-4-carboxylic acid is said to be deprotected, under conditions almost identical to those used in Example 27, to obtain the title compound.

H-NMR (D ₂ O) δ: 3.46 (d, 1H, J = 18), 4.02 (d, 1H, J = 18), 4.16 (2H), 4.70 (2H) , 5.52 (d, 9

1H, J = 5), 6.03 (d, 1H, J = 5), 7.76 (d, 1H, J = 6), 8.66 (d, 1H, J = 6), 8.78 ( s, 1H).

Example 39. (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- 11 (hydroxyimino) acetamido] -3- (3- (4-) trifluoroacetate acid salt amino-2- (Z) -buten-1-yl) pyrid-4-ylthio) -3-cephem-4-carboxylic acid

(7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (triphenylmethoxy-13 imino) acetamido] -3- (3- (4-) acid diphenylmethyl ester. Ter (-butoxycarbonylamino-2- (Z) -buten-1-yl) pyrid-4-ylthio) -3-cefem-4-carboxylic acid is said to be deprotected, under conditions almost identical to those used in Example 27, to obtain the compound of title, in the form of a mixture with the 1-butenyl isomer.

H-NMR (D ₂ O) δ: 3.46 (d, 1H, J = 18), 3.91 (2H), 4.02 (d, 1H, J = 18), 4.56 (2H) , 5.52 (d, 1H, 17 J = 5), 5.63 (2H), 6.03 (d, 1H, J = 5), 7.76 (d, 1H, J = 6), 8, 65 (d, 1H, J = 6), 8.76 (s, 1H).

Example 40. 3- (N-tert-Butoxycarbonylaminoethylsulfenylmethyl) -4-chloropyridine 19

To a solution of 3- (N-teȚ-butoxycarbonylaminoethyl) thiomethyl) -4-chloropyridine (687mg, 2.26 mmol) in methylene chloride (10ml) at 0 * C, 3-chloroperoxybenzoic acid (467, 21) is added. 2.72 mmol). After the reaction, overnight at room temperature, the reaction mixture is partitioned between dichloromethane and dilute sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated. Crystallization of the crude product from ethyl acetate / hexane leads to the title compound. 25 'H-NMR (CDCl ₃ ) δ: 1.40 (s, 9H), 2.90 (m, 1H), 3.01 (m, 1H), 3.59 (m, 2H), 4.00 (d, 1H,

J = 13), 4.22 (d, 1H, J = 13), 5.30 (wide s, 1H), 7.40 (d, 1H, J = 4), 8.45 (d, 1H, J = 4), 8.57 (s, 1H). 27

Example 41. (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2 (hydroxyimino) acetamido] -3- (3-aminoethylsulfenylmethylpyrid-4-) trifluoroacetate salt. iltio) -3-cefem-4-carboxylic 29 under conditions almost identical to those used in Example 43, (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazole-4-) diphenylmethyl ester. il) -2- (triphenylmethoxy-imino) acetamido] -3-mercapto-3-ce- 31 fem-4-carboxylic acid reacts with 3- (N-iron-butoxycarbonylaminoethylsulfenylmethyl) -4-chloropyridine to obtain diphenylmethyl ester of acid. (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- 33 (triphenylmethoxy-imino) acetamido] -3- (3-N-tert-butoxy-carbonylaminoethylsulfenylmethylpyrid -4-ylthio) -3cefem-4-carboxylic acid, which is then subjected to deprotection, under conditions almost identical to those used in Example 35, to obtain the title compound.

H-NMR (D ₂ O) δ: 2.90 (s, 3H), 3.20-3.35 (m, 1H), 3.50-3.70 (m, 4H), 4.00 ( dd, 1H, 37 J = 18.3), 4.55 (dd, 1H, J = 13.3), 4.65 (dd, 1H, J = 13.3), 5.51 (m, 1H) , 6.02 (m, 1H), 7.75 (m, 1H), 8.60 (m, 2H). 39

Example 42. (7R) -7 - {[2- [N, N'-bis- (t-butoxy-carbonyl) guadinino] ethylthio] acetyl] amino} -3- (4-chloromethyl-) 4-methoxybenzyl acid ester. 1,2,3-thiadiazol-5-ylthio) -3-cefem-4-carboxylic 41

To a solution of (7R) -7-amino-3- (4-chloromethyl-1,2,31,2,3-thiadiazole-5-ylthio) -3-cefem-4-carboxylic acid 4-methoxybenzylic ester ( 485 mg, 0.794 mmol) and {2- [N ^w , N ^w, -b / s- (Fbutoxy 43 carbonyl) guadinino] ethyl) thioacetic acid (329 mg, 0.873 mmol), phosphorus oxychloride (0.103 ml, added 1.11 mmol) and diisopropylethylamine (0.55 ml, 3.18 mmol) and stirred at -10'C for 45

h. Add water and extract the mixture with ethyl acetate. The organic extract was washed with aqueous sodium bicarbonate and then concentrated. The residue was purified by p-chromatography on 47 silica gel (1% methanol / dichloromethane) to afford 440 mg of the title compound.

RO 119830 Β1 'H-NMR (CD ₃ OD) δ: 1.44 (s, 9H), 1.47 (s, 9H), 2.79 (m, 2H), 3.30 (2H, superimposed on the solvent ), 3.35 (d, 1H, J = 18), 3.57 (m, 2H), 3.64 (d, 1H, J = 18), 3; 77 (s, 3H), 4.96 ( s, 2H), 5.15 (d,

1H, J = 5), 5.20 (d, 1H, J = 12), 5.23 (d, 1H, J = 12), 5.77 (d, 1H, J = 5), 6.81 ( d, 2H, J = 9), 7.25 (d, 1H,

J = 8).

Example 43. Iodide salt of 4-methoxybenzylic ester of (7R) -7 - {[2- [N, N'-bis (t-butoxycarbonyl) guadinino] ethylthio] acetyl] amino} -3- (4-isothiouronium) methylthiomethyl-1,2,3-thiadiazol-5iltio) -3-cephem-4-carboxylic acid

A solution of (7R) -7 - {[2- [N, N'-b / s- (Fbutoxycarbonyl) guadinino] ethylthio] acetyl] amino} -3- (4-chloromethyl-1, 4-methoxybenzyl acid ester solution. 2,3-1,2,3-thiadiazol-5-ylthio) -3-cefem-4-carboxylic acid (200 mg, 0.24 mmol), thiourea (18 mg, 0.24 mmol) and sodium iodide (35 mg, 0.24 mmol) in acetonitrile (3 mL) was stirred at room temperature overnight. The mixture is concentrated and triturated with dichloromethane. The residue was redissolved in acetone (2 ml) and filtered. The filtrate was concentrated to dryness to obtain 200 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (s, 18), 2.81 (m, 2H), 3.15 (d, 1H, J = 18), 3.36 (d, 1H, J = 15), 3.55 (d, 1, J = 15), 3.62 (m, 2H), 3.80 (s, 3H), 3.83 (d, 1H, J = 18), 4, 80 (d, 1H, J = 15), 4.86 (d, 1H, J = 15), 5.08 (d, 1H, J = 5), 5.23 (d, 1H, J = 12), 5.27 (d, 1H, J = 12), 5.58 (dd, 1H, J = 5.8), 6.85 (d, 2H, J = 9), 7.37 (d, 2H, J = 9), 8.24 (d, 1H, J = 8).

Example 44. (7R) -7 - {- ((2-Guadininoethylthio) acetyl] -amino} -3- (4-isothiouroniumethylthiomethyl-1,2,3-thiadiazole-5-ylthio) 2,2-dichloroacetate salt 3-cephem-4-carboxylic acid

A solution of (7R) -7 - {[2- [N, N'-b / s- (F-butoxycarbonyl) guadinino] ethylthio] acetyl] -amino} -3- (4-methoxybenzyl acid iodide salt solution) -isothiouronium ethylthio-methyl-1,2,3-1,2,3-thiadiazol5-ylthio) -3-cefem-4-carboxylic acid (200 mg) and anisole (0.1 ml) in dichloroacetic acid (2 ml) is stirred at room temperature for 16 h. The mixture is precipitated with diethyl ether / hexane, filtered and dried in vacuo to give 70 mg of the title compound.

Using methods almost identical to those described in the examples above, the following compounds are further prepared:

Example 45. (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- [3- (2-aminoethylthio) pyrid-4 acid trifluoroacetate salt ynylthio] -3-cephem-4-carboxylic acid

Example 46. (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- [3- (2-guanidinoethylthio) pyrid-4 acid trifluoroacetate salt -thio] -3-cefem-4 carboxylic acid

Example 47. (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- [3- (2-N- (iminomethyl) acid trifluoroacetate salt) aminoetiltio) pyrid-4-ylthio] -3-cephem-4-carboxylic acid

Example 48. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2 (hydroxyimino) acetamido] -3- [3- (2-aminopropylthio) pyrid4 -thio] -3-cefem-4-carboxylic acid

Example 49. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2 (hydroxyimino) acetamido] -3- [3- (2-guanidinopropylthio) pyrid -4-ylthio] -3-cephem-4-carboxylic acid

Example 50. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2 (hydroxyimino) acetamido] -3- [3 (2-N- (iminomethyl) ) aminopropiltio) pyrid-4-ylthio) -3-cephem-4-carboxylic acid

Example 51. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2 (hydroxyimino) acetamido] -3- [3- (2-amino-2) -carboxamidoetiltio) pyrid-4-ylthio] -3-cephem-4-carboxylic acid

Example 52. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2 (hydroxyimino) acetamido] -3- [3- (2-guanidino-2) -carboxamidoetiltio) pyrid-4-ylthio-3-cephem-4-carboxylic acid

Example 53. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2 (hydroxyimino) acetamido] -3- [3- (2-N- ( iminomethyl) amino-2-carboxamido-ethylthio) pyrid-4-ylthio] -3-cephem-4-carboxylic acid

Example 54. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2 (hydroxyimino) acetamido] -3- [3- (2-amino-3) -hidroxipropiltio) pyrid-4-ylthio] -3-cephem-4-carboxylic acid

RO 119830 Β1

Example 55. (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- 1 (hydroxyimino) acetamido] -3- [3- (2-guanidino acid) trifluoroacetic acid salt 3-hydroxypropylthio) pyrid-4-ylthio] -3-cephem-4-carboxylic acid

Example 56. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2-3 (hydroxyimino) acetamido] -3- [3- (2-N) - (iminomethyl) amino-3-hydroxypropyl-thio) pyrid-4-ylthio] -3-cephem-4carboxilic5

Example 57. The trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazzo-4-yl) -2 (hydroxyimino) acetamido] -3- [3- (2-aminoethylthiomethyl) pyrid-4 ynylthio] -3-cephem-4-carboxilic7

Example! 58. The trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2 (hydroxyimino) acetamidol-3- [3- (2-guanidinoethylthiomethyl) pyrid-4 ynylthio] -3-cephem-4-carboxilic9

Example 59. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2 (hydroxyimino) acetamido] -3- [3- (2-N- ( iminomethyl) aminoethylthiomethyl) pyrid-4-ylthio] -3-cefem-4-11 carboxylic acid

Example 60. (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- 13 (hydroxyimino) acetamido] -3- [3 '(2-aminopropylthiomethyl) trifluoroacetic acid salt ) pyrid-4-ylthio] -3-cephem-4-carboxylic acid

Example 61. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- 15 (hydroxyimino) acetamido] -3- [3- (2-guanidinopropylthiomethyl) pyrid -4-ylthio] -3-cephem-4-carboxylic acid

Example 62. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- 17 (hydroxyimino) acetamido] -3- [3- (2-N) - (iminomethyl) aminopropylthiomethyl) -pyrid-4-ylthio] -3-cefem-4-carboxylic 19

Example 63. (7R) -7 - [(Z) -2- (2-aminothiazole-4-H) -2 (hydroxyimino) acetamido-3- [3- (2-amino-2-) trifluoroacetic acid salt. carboxamidoethylthiomethyl) pyrid-4-Hthio] -3-cefem-4-21 carboxylic acid

Example 64. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- 23 (hydroxyimino) acetamido] -3- [3- (2-guanidino) -2-carboxamidoethylthiomethyl) -pyrid-4-ylthio] -3-cefem-4-carboxylic 25

Example 65. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2 (hydroxyimino) acetamido] -3- [3- (2-N- ( iminomethyl) amino-2-carboxamido-ethylthiomethyl) pyrid-4-ylthio] -3-27 cefem-4-carboxylic acid

Example 66. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- 29 (hydroxyimino) acetamido] -3- [3-2-amino- 3-hydroxypropylthiomethyl) pyrid-4-ylthio] -3-cephem-4-carboxylic acid

Example 67. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- 31 (hydroxyimino) acetamido] -3- [3- (2-guanidino) -3-hydroxypropylthiomethyl) -pyrid-4-ylthio] -3-cefem-4-carboxylic 33

Example 68. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2 (hydroxyimino) acetamido] -3- [3- (2-N- ( iminometH) amino-3-hydroxypropyl-thiomethyl) pyrid-4-ylthio] -3-35 cefem-4-carboxylic acid

Example 69. The trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothia-37 zol-4-yl) -2- (hydroxyimino) acetamido] -3- [ 3- (2-aminoetiltio) pyrid-4-ylthio] -3-cephem-4-carboxylic acid

Example 70. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothia-39 zol-4-yl) -2- (hydroxyimino) acetamido] -3- [ 3- (2-guanidinoetiltio) pyrid-4-ylthio] -3-cephem-4-carboxylic acid

Example 71. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothia-41 zol-4-yl) -2- (hydroxyimino) acetamido] -3- [ 3- (2-N- (iminomethyl) aminoethylthio) pyrid-4-ylthio] -3-cefem4carboxylic 43

Example 72. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- [3- ( 2 ^, aminopropylthio) pyrid-4-ylthio] -3-cefem-4-carboxylic acid 45

Example 73. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxyirnino) acetamido] -3- [3- ( 2-Guanidinopropylthio) pyrid-4-Hthio] -3-cefem-4-carboxylic acid 47 ---------- Example 74. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2 - (2-amino-5-chlorothiazole -4-yl) -2- (hydroxyimino) acetamido] -3- [3- (2-N- (iminomethyl) amino-propylthio) pyrid-4-ylthio] -3-cefem -4- 49 carboxylic acid

RO 119830 Β1

Example 75. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazole acid)

-4-yl) -2- (hydroxyimino) acetamido] -3- [3- (2-amino-ethylthio-2-carboxamido) pyridin-4-ylthio] -3-cephem-4-carboxylic acid

Example 76. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- [3- (2- guanidino-2-carboxy-amidoetiltio) pyrid-4-ylthio] -

3-cefem-4-carboxylic acid

Example 77. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol -4-yl) -2- (hydroxyimino) acetamido] -3- [3 '( 2-N- (iminomethyl) amino-2-carboxamidoetiltio) pyrid-4-ylthio] -3-cephem-4-carboxylic acid

Example 78. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2 ~ (2-amino-5-chlorothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- [3- (2- amino-3-hydroxypropyl-thio) pyrid-4-ylthio] -3-cephem-4-carboxylic acid

Example 79. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- [3- (2- hidroxhpropiltio-3-guanidino) pyrid-4-ylthio] -3-cephem-4-carboxylic acid

Example 80. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol -4-yl) -2- (hydroxyimino) acetamido] -3- [3- (2 N- (iminomethyl) amino-3-hydroxypropylthio) pyrid-4-ylthio] -3-cephem-4-carboxylic acid

Example 81. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- [3- ( 2-aminoetHtiometil) pyrid-4-ylthio] -3-cephem-4-carboxylic acid

Example 82. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol -4-yl) -2- (hydroxyimino) acetamido] -3- [3 (2 -guanidinoetiltiometil) pyrid-4-ylthio] -3-cephem-4-carboxylic acid

Example 83. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol -4-yl) -2- (hydroxyimino) acetamido] -3- [3- (2 N- (iminomethyl) aminoethyl-thiomethyl) pyrid-4-ylthio] -3-cephem-4-carboxylic acid

Example 84. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazzoic acid) salt

4- yl) -2- (hydroxyimino) acetamido] -3- [3- (2-aminopropylthiomethyl) pyrid-4-ylthio] -3-cefem-4-carboxylic acid

Example 85. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol -4-yl) -2- (hydroxyimino) acetamido] 3- [3- (2 -guanidinopropiltio-methyl) pyrid-4-ylthio] -3'Cefem-4-carboxylic acid

Example 86. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol -4-yl) -2- (hydroxyimino) acetamido] -3- [3- ( 2-N- (iminomethyl) amino-propylthiomethyl) pyrid-4-ylthio] -3-cephem-4-carboxylic acid

Example 87. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol -4-yl) -2- (hydroxyimino) acetamido] -3- [3- ( 2-amino-2-carboxamido-etHtiometil) pyrid-4-ylthio] -3-cephem-4-carboxylic acid

Example 88. The trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol -4-yl) -2- (hydroxyimino) acetamido] -3- [3- ( 2-guanidino-2-carboxy-amidoetiltiometil) pyrid-4-Htio] -3-cephem-4-carboxylic acid

Example 89. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol -4-yl) -2- (hydroxyimino) acetamido] -3-3- (2 -N- (iminomethyl) amino-2-carboxamidoethylthiomethyl) pyrid-4-thio] -3-cefem-4-rboxylic acid

Example 90. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-c-orothiazol-4-yl) 2- (hydroxyirnino) acetamido] -3- [3- (2-Amino-3-hydroxypropyl-thiomethyl) pyrid-4-ylthio] -3-cefem-4-carboxylic acid

Example 91. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chloroiiazole acid)

-4-yl) -2- (hydroxyimino) acetamido] -3- [3- (2-guanidino-3-hydroxy-propylthiomethyl) pyrid-4-ylthio] -3-cephem-4-carboxylic acid

RO 119830 Β1

Example 92. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazole 1)

-4-yl) -2- (hydroxyimino) acetamido] -3- [3- (2-N- (iminomethyl) amino-3-hydroxypropylthiomethyl) pyrid-4-ylthio] 3-cefem-4-carboxylic 3

Example 93. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2 (2-fluoroethoxyimino) acetamido] -3- [3- (2-aminoethylthio) ) pyrid-4-ylthio] -3-cefem-4-carboxylic acid 5

Example 94. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2 (2-fluoroethoxyimino) acetamido] -3- [3- (2-guanidinoethylthio) ) pyrid-4-ylthio] -3-cefem-4-carboxylic acid 7

Example 95. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2 (2-fluoroethoxyimino) acetamido] -3- [3- (2-N) - (iminomethyl) aminoethylthio) pyrid-4-ylthio] -3-cefem-4-9 carboxylic acid

Example 96. The trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- 11 (2-fluoroethoxyimino) acetamido] -3- [3- (2 -aminopropiltio) pyrid-4-ylthio] -3-cephem-4-carboxHic

Example 97. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- 13 (2-fluoroethoxyimino) acetamido] -3- [3- (2 -guanidinopropiltio) pyrid-4-ylthio] -3-cephem-4-carboxylic acid

Example 98. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- 15 (2-fluoroethoxyimino) acetamido] -3- [3- (2 -N- (iminomethyl) aminopropylthio) -pyrid-4-ylthio] -3-cefem-4-carboxylic 17

Example 99. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2 (2-fluoroethoxyimino) acetamido] -3- [3- (2-amino) -2-carboxamidoethylthio) -pyrid-4-Hthio] -3-cefem-4- 19 carboxylic acid

Example 100. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) - 21

2- (2-Fluoroethoxyimino) acetamido] -3- [3- (2-guanidino-2-carboxamidoethyl-thio) pyrid-4-ylthio] -3-cefem-4-carboxylic 23

Example 101. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -

2- (2-fluoroethoxyimino) acetamido] -3- [3- (2-N- (iminomethyl) amino-2-carboxamidoethylthio) pyrid-4-ylthio] - 25

3-cefem-4-carboxylic acid

Example 102. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) ~ 27

2- (2-Fluoroethoxyimino) acetamido] -3- [3- (2-amino-3-hydroxypropylthio) pyrid-4-ylthio] -3-cefem-4-carboxylic 29

Example 103. (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) 2- (2-fluoro-ethoxyimino) acetamido] -3- [3- (2-guanidino acid) trifluoroacetic acid salt -3-hydroxypropyl) -pyrid-4-ylthio] -3-cefem-4- 31 carboxylic acid

Example 104. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) - 33 2- (2-fluoroethoxyimino) acetamido] -3- [3- (2 -N- (iminomethyl) amino-3-hydroxy-propylthio) pyrid-4-yl] thio-3-hexaf-4-carboxylic 35

Example 105. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) 2- (2-fluoroethoxyimino) acetamido] -3- [3- (2-aminoethylthiometH) H ) pyrid-4-ylthio) -3-cefem-4-carboxylic 37

Example 106. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) 2- (2-fluoroethoxyimino) acetamido] -3- [3- (2-guanidinoethylthiomethyl) ) pyrid-4-yl-thio) -3-cefem-4-carboxylic 39

Example 107. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) 2- (2-fluoroethoxyimino) acetamido] -3- [3- (2-N) - (iminomethyl) aminoethylthiomethyl) -pyrid-4-ylthio] -3-cefem-4- 41 carboxylic acid

Example 108. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) - 43

2- (2-fluoroetoxiimino) acetamido] -3- [3- (2-aminopropiltiometil) pyrid-4-ylthio] -3-cephem-4-carboxylic acid

Example 109. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) - 45

2- (2-fluoroetoxiimino) acetamido] -3- [3- (2-guanidinopropHtiometil) pyrid-4-Htio] -3-cephem-4-carboxylic acid

Example 110. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) - 47

2- (2-Fluoroethoxyimino) acetamido] -3- [3- (2-t4 = (immoLTietyl) aminopropylthio-methyl-) pyrid-4-ylthio] -3-diphem-4-carboxylic acid 49

RO 119830 Β1

Example 111. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) acid

2- (2-fluoroetoxiimino) acetamido] -3- [3- (2-amino-2-methyl-carboxamidoetiltio) pyrid-4-ylthio] -3-cephem

4-carboxylic acid

Example 112. (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) 2- (2-fluoroethoxyimino) acetamido] -3- [3- (2-guanidino acid) trifluoroacetic acid salt -2-carboxamidoethylthiomethyl) pyrid-4-ylthio) -3 cefem-4-carboxylic acid

Example 113. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) 2- (2-fluoroethoxyimino) acetamido] -3- [3- (2'N - (iminomethyl) amino-2-carboxamido and thiomethyl) pyrid-4-ylthio] -3-cefem-4-carboxylic acid

Example 114. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) 2- (2-fluoroethoxyimino) acetamido] -3- [3- (2-amino) -3-hydroxypropylthiomethyl) pyrid-4-ylthio] -3-cefem-4 carboxylic acid

Example 115. Trifluoroacetic acid salt of (7R) -7- (Z) -2- (2-aminothiazole-4-H) 2- (2-fluoroethoxyimino) acetamido] -3- [3- (2-guanidino-) 3-methyl-hydroxypropylthio) pyrid-4-ylthio] -3-cephem

4-carboxylic acid

Example 116. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) acid

2- (2-fluoroethoxyimino) acetamido] -3- [3- (2-N- (iminomethyl) amino-3-hydroxy-propylthiomethyl) pyrid-4-ylthio]

3-cefem-4-carboxylic acid

Example 117. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazole zol-4-H) -2- (2-fluoroethoxyimino) acetamido] -3- [ 3- (2-aminoetiltio) pyrid-4-ylthio] -3-cephem-4-carboxylic acid

Example 118. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazole zol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3- [ 3- (2-Guanidinoethylthio) -pyrid-4-ylthio] -3-cefem-4 carboxylic acid

Example 119. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazole zol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3- [ 3- (2-N- (iminomethyl) -aminoethylthio) pyrid-4-ylthiol-3-cefem-4-carboxylic acid

Example 120. The trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3- [3- (2-AminopropHthio) pyrid-4-ylthio] -3-cefem-4 carboxylic acid

Example 121. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3- [3- (2-thio-guanidinopropyl) pyrid-4-ylthio] -3-cephem

4- carboxylic acid

Example 122. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazole zol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3- [ 3- (2-N- (iminometH) -aminopropylthio) pyrid-4-ylthio] -3 cefem-4-carboxylic acid

Example 123. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazole zol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3- [ 3- (2-amino-2-carbox-amidoethylthio) pyrid-4-ylthio] -3 cefem-4-carboxylic

Example 124. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazole zol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3- [ 3- (2-Guanidino-2-carboxamidoethylthio) pyrid-4-ylthio] -3 cefem-4-carboxylic

Example 125. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) acid

2- (2-fluoroethoxyimino) acetamido] -3- [3- (2-N- (iminomethyl) -amino-2-carboxamidoethylthio) pyrid-4-yl]

3-cefem-4-carboxylic acid

Example 126. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazole zol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3- [ 3- (2-amino-3-hydroxy-propylthio) pyridin-4-ylthio] -3-cephem

4- carboxylic acid

Example 127. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazole zol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3 '[ 3- (2-Guanidino-3-hydroxypropyl) pyrid-4-Htio] -3 cefem-4-carboxylic

RO 119830 Β1

Example 128. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothia-1 zol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3 - [3- (2-N- (iminomethyl) amino-3-hydroxypropylthio) pyrid-4-ylthio] -3-cephem-4-carboxilic3

Example 129. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3- [3 - (2-aminoethylthiomethyl) -pyrid-4-ylthio] -3-cefem-4-5 carboxylic acid

Example 130. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chloro-7-zol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3 - [3- (2-guanidinoetiltio-methyl) pyrid-4-ylthio] -3-cephem-4carboxilic9

Example 131. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3- [3 - (2-N- (iminomethyl) -aminoethylthiomethyl) pyrid-4-ylthio] -3-11 cefem-4-carboxylic acid

Example 132. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothia-13 zol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3 - [3- (2-Aminopropylthio-methyl) pyrid-4-ylthio] -3-cefem-4-carboxylic acid 15

Example 133. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3- [3 - (2-Guanidinopropyl-thiomethyl) pyrid-4-ylthio] -3-cefem-4- 17 carboxylic acid

Example 134. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothia-19 zol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3 - [3- (2-N- (iminomethyl) -aminopropHthiomethyl) pyrid-4-ylthio] 3-cefem-4-carboxylic 21

Example 135. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3- [3 - (2-amino-2-carbox-amidoethylthiomethyl) pyrid-4-ylthio] -3-23 cefem-4-carboxylic acid

Example 136. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothia-25 zol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3 - [3- (2-Guanidino-2-carboxamidoethylthiomethyl) pyrid-4-thio] -3-cefem-4-carboxylic 27

Example 137. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3- [3 - (2-N- (iminomethyl) -amino-2-carboxamidoethylthio-29-yl) pyrid-4-ylthio] -3-cefem-4-carboxylic acid

Example 138. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothia-31 zol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3 - [3- (2-amino-3-hydroxy-propylthiometh) pyrid-4-ylthio] -3-cefem-4-carboxyl 33

Example 139. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (2-fluoroethoxyimino) acetmido] -3- [3 - (2-Guanidino-3-hydroxy-propyl thiomethyl) pyrid-4-ylthio] -3-35 cefem-4-carboxylic acid

Example 140. Trifluoroacetic acid salt of (7R) -7 - [(Z) -2- (2-amino-5-chlorothia-37 zol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3 - [3- (2-N- (iminomethyl) -amino-3-hydroxypropylthiomethyl) pyrid-4-ylthio] -3-cefem-4-carboxylic 39

Thus, it should be admitted that the compounds, methods and compositions of the invention are effective against different strains of lactam-resistant bacteria, which present an increased risk to society in terms of health.

Although certain embodiments and examples have been used to describe the invention, it will be apparent to one skilled in the art that modifications to the embodiments and the examples shown can be made without departing from the scope and spirit of this invention. 45

These references that have not been included here, including both patent and non-patent references, are expressly incorporated herein as references for all purposes. 47

Claims (19)

claims 1. Compound of formula: or a pharmaceutically acceptable salt thereof, characterized in that R ¹ is selected from the group consisting of -NHC (O) ZR ³ , -NR ⁴ R ⁵ , and Z is selected from the group consisting of -CH ₂ (X) _m -, -C (NOR ⁶ ) -, -CH (OR ⁷ ) -, -C (CHCO ₂ R ⁸ ) - and -CH (NR ⁹ R ¹⁰ ) -; X is selected from the group consisting of oxygen and sulfur; m is selected from the group consisting of 0 and 1; R ³ is selected from the group consisting of cyan, Ο, -Οθ alkyl which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromine, fluorine, chlorine, iodine, mercapto or thio, cyano, alkylthio C, - C ₆ , heterocycle selected from the group comprising fur, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzofuranyl and dibenzothienyl, aryl C ₆ -C ₁₄ , heteroaryl, carboxyl, alkoxycarbonyl Ο, -CC, alkyl Ο , C ₂ -C ₆ alkenyl, nitro, amino, alkoxyl Ο _Γ Ο ₆ and amido; aryl C ₆ -C ₁₄ , which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromine, fluorine, chlorine, iodine, mercapto or thio, cyano, alkylthio Ο, -Οθ, heterocycle selected from the group comprising furyls , thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazoly, piperazinyl, dibenzofuranil and dibenzothienyl, aryl C ₆ -C ₁₄ , heteroaryl, carboxyl, alkoxycarbonyl C, C ₆ , alkyl Ο, -Ο, -, alkenyl C ₂ -C ₆ , nitro, amino, alkoxyl C, -C ₆ and amido; aryl C ₆ -C ₁₄ , which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromine, fluorine, chlorine, iodine, mercapto or thio, cyano, cyanamido, C 1 -C ₆ alkyl, heterocycle selected from the group comprising fur, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzofuranil and dibenzothienyl, aryl C ₆ -C ₁₄ , heteroaryl, carboxyl, alkoxycarbonyl C, -C ₆ , alkyl 0, -0 ₆ , alkenyl C ₂ -C ₆ , nitro, amino, C-alkoxyl, -C ₆ and amido; a heterocycle selected from the group comprising fur, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzofuranil and dibenzothienyl, which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromine, fluorine, fluorine, , mercapto or thio, cyano, cyanamido, C ₁ -C ₆ alkylthio, heterocycle, C ₆ -C ₁₄ aryl, heteroaryl, carboxyl, oxo, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, nitro, amino, alkoxyl C, -C ₆ and amido; or a heteroalkyl group (RHetAr), wherein R is C, -C ₆ alkyl; HetAr is an aromatic heterocycle defined as above), and (CH ₂ ) _n T, wherein n is 1 to 6; T is selected from the group consisting of amino NRR 'wherein R and R' may be C 0 -C, C ₆ -C _14L aryl or acyl C (O) R, wherein R is _Cj-C6 alkyl, amidino (bonded to C- or N-), guanidino, and isothioureido, which may be substituted with 0, -0 ₆ alkyl, C ₆ -C ₁₄ aryl, hydroxyl, or amino, as defined above; R ⁴ ' ⁷ are independently selected from the group consisting of hydrogen, C 1 -C ₆ alkyl, C ₆ C ₁₄ aryl and acyl, as defined above; wherein R ⁶ may also be a group forming a hydroxy group, protected by the adjacent oxygen atom; R ⁸ is selected from hydrogen, C 1 -C ₆ alkyl, C ₆ -C ₁₄ aryl; R ⁹ and R ¹⁰ are independently selected from the group consisting of hydrogen, alkyl Ο, -Ορ, acyl, RO 119830 Β1 as defined above, and heterocyclylcarbonyl (C (O) Het, wherein Het is a heterocycle as 1 defined above); R ² is selected from the group consisting of hydrogen, substitutable Ο, -Οθ alkyl, 3 as defined above, C 2 -C 6 alkenyl, which can be substituted with one or more functional groups, selected from the group consisting of hydroxyl, bromine, fluorine, chlorine, iodine, mercapto or thio, 5 cyano, achylthioCj-Cg, heterocycle, aryl C6-C14, heteroaryl, carboxyl, alkoxycarbonyl Ο, -Οθ, alkyl Ο, -Ο6, alkenyl C2-C6, nitro , amino, alkoxyl C, -C6, and amido; aryl C6-C14 which can be substituted as 7 defined above, a hetocycle which can be substituted, as defined above, aralkyl (RAr wherein R is C, -C6 alkyl, which can be substituted, as defined above and Ar is 9 aryl C6-C, 4, which can be substituted, as defined above), heteroaralkyl, and trialkylsilyl (R'RSi, wherein R, R 'and R are alkyl groups 0, -06); or R ² is not present and the CO2 group 11 to which they could be attached covers a negative charge; the ring G, H, J, L and M is a carbon, nitrogen or NR ¹¹ (quaternary ammonium heterocycle), 13 containing a heterocycle selected from the group consisting of pyridinyl, piperazinyl, pyrimidinyl and pyrazinyl; 15 R ¹¹ is selected from the group consisting of H, halogen, C, -C ₆ alkyl, Ο, -Ο ₆ alkoxy, hydroxyl, amino as defined above, cyano, hydroxyalkyl Ο, -Ο ₆ , carboxamidoalkyl Ο, -Ο ₆ , amino-17-chlΟ, -Cg or C-alkyl, -C _6- quaternary ammonium, and quaternary heteroarylalkyl; alk, and alk ₂ are C, -C ₆ alkyl groups, which can be independently substituted with a substituent 19 selected from the group consisting of Ο, -Ο ₆ alkyl, hydroxyl, amino, as defined above, C 1 -C 6 alkoxy. , hydroxyalkyl Ο, -Ο ₆ and carboxamide; 21 over 0.1, or 2; R is selected from the group consisting of sulfur, SO, SO ₂ , NH, N-alkyl C, -C ₆ , oxygen, C = C 23 (cis or trans), and C = C; q is 1; 25 R is 0.1,2 or 3; R ¹² is NR ¹³ R ¹⁴ 27 Ai. f4 R ¹³ -R ¹⁶ are independently selected from the group consisting of H, hydroxy, amino as defined above, amidino, alkyl Ο, -Ο ₆ , cycloalkyl Ο, -Ο ₆ , acyl, aminoacyl and phosphoryl and, taken together, they can form a ring of 5 or 6 members; and 43 R ¹⁷ is H, or alkyl Ο, -Οθ; wherein alic, and R ¹² , taken together, may form an optionally substituted 5 or 45 6 member non-aromatic heterocycle, which may be substituted, as defined above. A compound or salt according to claim 1, characterized in that R ¹ is -47 NHC (O) ZR ³ . A compound or salt according to claim 2, characterized in that R ³ is C ₆ -49 C ₁₄ aryl or substitutable heterocycle, as defined in claim 1. RO 119830 Β1 A compound or salt according to claim 3, characterized in that R ³ is selected from the group consisting of phenyl, thienyl or furanyl, which can be substituted, as defined in claim 1,2-aminothiazol-4-yl, 2-. amino-5-chlorothiazol-4-yl, and 2-aminothiadiazol-4-yl. A compound or salt according to claim 4, characterized in that Z is C (NOR ⁶ ) -, and R ⁶ is selected from the group consisting of hydrogen and C, -C ₆ alkyl, which can be substituted, as defined in claim 1. A compound or salt according to claim 5, characterized in that R ⁶ is selected from the group consisting of hydrogen, 2-fluoroethyl, cyclopropylmethyl, allyl, dichloroalyl and cyclopentyl and R ³ is selected from the group consisting of phenyl, 2-thienyl, 2 -furyl, 2-aminothiazol-4-yl, 2-amino-5-chlorothiazol-4-yl, and 2-aminothiadiazol-4-yl. A compound or salt according to claim 6, characterized in that R ⁶ is hydrogen or 2-fluoroethyl, and R ³ is 2-aminothiazol-4-yl, or 2-amino-5-chlorothiazol-4-yl. A compound or salt according to claim 7, characterized in that said compound is active against methicillin-resistant, vancomycin-resistant or ampicillin-resistant bacteria, as demonstrated by a lower inhibitory concentration than that of cefotaxim or imipenem. . A compound or salt according to claim 1, characterized in that R ¹ is -NHC (O) ZR ³ ; Z is -C (NOR ⁶ ); R ⁶ is hydrogen or fluoroethyl; R ³ is a heterocycle, which can be substituted, as defined in claim 1; R ² is hydrogen, or the CO2 group to which it could be attached covers a negative charge; G, H, L and M are carbon atoms; J is nitrogen; alk ₄ is CH ₂ ; p is 0 or 1; R is sulfur; q is 1; alk ₂ is CH ₂ ; R is 2 or 3; R ¹² is NH ₂ or NH ₃ +; and there are zero groups R ¹¹ and one group [(alki) _p (R) _q (alk ₂ ) _r R ¹² J. A compound or salt according to claim 9, characterized in that R ³ is selected from the group consisting of 2-aminothiazol-4-yl, 2-amino-5-chlorothiazol-4-yl, and 2-aminothiadiazol-4-yl. A compound or salt according to claim 9, characterized in that said compound or salt is: (7R) -7- [(Z-2- (2-amino-5-chloro-thiazol-4-yl) -2- (hydroxyimino) acetamido] -3- [3- (2-aminoetiltiometil) pyrid-4-ylthio] - 3-cefem-4-carboxylate, or a suitable salt, (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- [3- ( 2-aminoethylthiomethyl) pyrid-4-ylthio] -3-cefem-4-carboxylate, or a corresponding salt, (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- [3- (2-aminoethylthio) pyrid-4-ylthio] -3-cefem-4-carboxylate, or a corresponding salt, (7R) -7 - [(Z) - 2- (2-amino-5-chloro-thiazol-4-yl) -2- (hydroxyimino) acetamido] -3- [3- (2R-2-amino-2carboxamidoetiltiometil) pyrid-4-ylthio] -3-cephem-4 -carboxylate, or an appropriate salt, (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- [3- (2S -2-amino-2-carboxamidoethylthiomethyl) pyrid-4-ylthio] -3-cefem-4-carboxylate, or a corresponding salt, (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazole-4 -yl) -2- (hydroxyimino) acetamido] -3- (3- (2R-2-amino-3hydroxypropylthiomethyl) pyrid-4-ylthio) -3-cefem-4-carboxylate, or a corresponding salt thereof It has, RO 119830 Β1 (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- [3- (2S-2-amino- 3- 1 hydroxypropylthiomethyl) pyrid-4-ylthio] -3-cefem-4-carboxylate, or a corresponding salt, (7R) -7 - [(Z) -2- (2-amino-5-chlorothiazol-4-yl ) -2- (2-fluoroethoxyimino) acetamido] -3- [3- (2-amino-3 ethylthiomethyl) pyrid-4-ylthio] -3-cefem-4-carboxylate, or a corresponding salt, (7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (2-fluoroethoxyimino) acetamido] -3- [3- (2-aminoethylthio-5-methyl) pyrid-4-ylthio] -3- cefem-4-carboxylate, or an appropriate salt thereof. A compound according to claim 1, of the formula: 7 13 or a pharmaceutically acceptable salt thereof, characterized in that 15 R ³⁴ is halogen or hydrogen; R ⁵³ is selected from the group consisting of NH ₂ and protected amino; and 17 R ² , R ⁶ , G, J, L, M, R ¹¹ , alki, p, R, q, alk ₂ , r, and R ¹² are as defined in claim 1 above.19 13. A compound or salt according to claim 12, characterized in that R ² is hydrogen or is not present and the CO ₂ group to which it could be attached carries a negative charge; 21 R ³⁴ is chlorine, or hydrogen; R ⁶ is hydrogen, cyclopentyl, or fluoroethyl; 23 G, H, J, L, and M are selected to form 2-pyridyl, 3-pyridyl, 3-pyridyl, or 4-pyridyl; R ¹¹ is hydrogen, halogen, or alkyl; there is only one group [(alkJpțR ^ qțalkJrR ¹² )]; alk, is CH ₂ ; 27 p is 0 or 1; R is sulfur; 29 q is 1; alk ₂ is CH ₂ optionally substituted with hydroxy, C 1 -C 6 hydroxyalkyl, or carboxamide; 31 residues 2; and R ¹² is NH ₂ .33 14. A compound or salt according to claim 13, characterized in that R ³⁴ is chlorine, R ⁶ is hydrogen, and G, H, J, L, and M are selected to form 4-pyridyl.35 Use of a compound according to any one of claims 1 ... 14, or a salt thereof, in the manufacture of a medicament for the treatment of a mammal suffering from methicillin-resistant, lavancomycin-resistant, or ampicillin-resistant bacterial infection. Use according to claim 15, wherein said mammal is infected with a methicillin-resistant or ampicillin-resistant enterococcus. 17. Antibacterial composition, for treating a bacterial infection, methicillin-resistant, vancomycin-resistant or ampicillin-resistant, comprising a compound or salt, as defined in any of claims 1-14 in an acceptable carrier. ve- 43 pharmaceutical dosage. The composition of claim 17, wherein said infection is produced by a methicillin-resistant staphylococcus, or ampicillin-resistant enterococcus. 19. Compound of formula: 47 EN 119830 Β1 or a salt thereof, pharmaceutically acceptable, characterized in that R 'is selected from the group consisting of -NHC (O) ZR ³ , -NR ⁴ R ⁵ , and Z is selected from the group consisting of -CH ₂ (X) _m -, -C (NOR ⁶ ) -, -CH (OR ⁷ ) -, - (CHCO ₂ R ⁸ ) and -CH (NR ⁹ R ¹⁰ ) -; X is selected from the group consisting of oxygen and sulfur; m is selected from the group consisting of 0 and 1; R ³ is selected from the group consisting of cyan, 0, -0 ₆ alkyl which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromine, fluorine, chlorine, iodine, mercapto or thio, cyano, alkylthio Ο, -Οθ, heterocycle selected from the group comprising fur, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzofuranyl and dibenzothienyl, aryl C ₆ -C ₁₄ , heteroaryl, carboxyl, alkoxycarbonyl Ο, -Ο ₆ , alkyl Ο ₆ , C ₂ -C ₆ alkenyl, nitro, amino, alkoxyl Ο, -Οθ and amido; aryl C ₆ -C ₁₄ which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromine, fluorine, chlorine, iodine, mercapto or thio, cyano, cyanamido, alkylthio Ο, -Οθ, heterocyclic selected from the group comprising fur, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzofuranil and dibenzothienyl, aryl C ₆ -C ₁₄ , heteroaryl, carboxyl, alkoxycarbonyl 0, C ₆ , alkyl Ο, -Οθ, alkenyl C ₂ -C ₆ , nitro, amino, alkoxyl Ο, -Ο ₆ and amido; a heterocycle selected from the group comprising fur, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzophyranes and dibenzothienyl, which may be substituted by one or more substituents selected from the group consisting of hydroxyl, chlorine, fluorine, bromine, bromine, , mercapto or thio, cyano, cyanamido, alkylthio (Ț-Cg, heterocycle, aryl C ₆ -C ₁₄ , heteroaryl, carboxyl, alkoxycarbonyl Ο, -Ο ₆ , alkyl Ο, -Οθ alkenyl C ₂ -C ₆ , nitro, amino , alkoxyl 0, -Cg and starch; a heterocycle selected from the group comprising fur, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzofuranyl and dibenzothienyl, aryl C ₆ -C ₁₄ , heteroaryl, carboxyl, alkoxycarbonyl C ₁ -C 9, alkyl, C 1-6 alkyl, -Cg, nitro, amino, C1-C6 alkoxyl and amido; a heterocycle selected from the group comprising fur, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzofuranil and dibenzothienyl, which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromine, fluorine, fluorine, , mercapto or thio, cyan, cyanamido, Ο, -Cg alkylthio, heterocycle, C ₆ -C ₁₄ aryl, heteroaryl, carboxyl, oxo, alkoxycarbonyl Ο, -Οθ, alkyl Ο, -Οθ, C ₂ -C ₆ alkenyl, nitro , amino, alkoxyl Ο, -Ο ₆ and amido; or a heteroalkyl group (RHetAr), wherein R is Ο, -Cg alkyl; HetAR is an aromatic heterocycle defined as above), and (CH ₂ ) _n T; n is 1 to 6; T is selected from the group consisting of amino NR'R, wherein R 'and R' may be 0, -Cg alkyl, amidino (C-, or N- linked), guanidino, and isothiourido, which may be substituted with alkyl. CȚ-Cg, C ₆ -C ₁₄ aryl, hydroxyl, or amino as defined above; R ⁴ ' ⁷ are independently selected from the group consisting of hydrogen, alkyl Ο, -Ο ₆ , aryl C ₆ -C ₁₄ and acyl, as defined above; wherein R ⁶ may also be a group which forms a hydroxy protecting group with adjacent oxygen; R ⁸ is selected from hydrogen, C ₁ -C ₆ alkyl, C ₆ -C ₁₄ aryl; R ⁹ and R ¹⁰ are independently selected from the group consisting of hydrogen, C 1 -C ₆ alkyl, acyl, RO 119830 Β1 as defined above, and heterocyclylcarbonyl (C (O) Het, wherein Het is a heterocycle as 1 defined above); R ² is selected from the group consisting of hydrogen, C 1 -C 6 alkyl which can be substituted, 3 as defined above, C 2 -C 6 alkenyl, which can be substituted with one or more functional groups, selected from the group consisting of hydroxyl, bromine, fluorine, chlorine, iodine, mercapto or thio, 5-cyano, C 1 -C 8 achylthio, heterocycle, C 6 -C 14 aryl, heteroaryl, carboxyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, nitro , amino, alkoxyl C, -C6, and amido; aryl C6-C14, which can be substituted as defined above 7, a heterocycle which can be substituted, as defined above, aralkyl (Rar, wherein R is C, -C6 alkyl, which can be substituted, as defined above and Ar is 9 C6-C14 aryl, which may be substituted as defined above), heteroaralkyl, and trialkylsilyl (R'RSi, wherein R, R 'and R are alkyl groups Ο, - Οβ); or R ² is not present and the CO2 group 11 to which it could be linked carries a negative charge; ring A, B, D, and E is a heterocycle containing a carbon, nitrogen, or sulfur atom selected from the group consisting of thienyl, imidazolyl, thiazolyl, thiadiazolyl and pyrazolyl; R ¹¹ is selected from the group consisting of H, halogen, C 1 -C ₆ alkyl, Ο, -Οβ alkoxy, hydroxyl, 15 amino, as defined above, cyano, C 1 -C 6 hydroxyalkyl, C, -C carboxamidoalkyl. ₆ , amino acid Ο, -Οβ, or quaternary alkylammonium Ο, -Οβ and heteroarylal quaternary alkyl; 17 alk, and alk ₂ are C, -C ₆ alkyl groups, which can be independently substituted with a substituent selected from the group consisting of C 1 -C 6 alkyl, hydroxyl, amino, as defined above, 19 Ο, -Οβ alkoxy C 1 -C 6 hydroxyalkyl and carboxamido; over 0.1, or 2; 21 R is selected from the group consisting of sulfur, SO, SO ₂ , NH, N-alkyl Ο, -Οθ, oxygen, CC (cis or trans), and C = C; 23